Rapid Point of Diagnostics Testing and Imaging 9781119282655, 1119282659, 9781119282686, 1119282683, 9781119282648

Table of contents :
Content: Part I The Health of Low- and Middle-Income Countries Today 1 1 The Burden of Communicable Diseases in Low- and Middle-Income Countries 3Kerry Atkinson and David Mabey 1.1 Introduction 4 1.2 Definition of a Communicable Disease 4 1.3 Definition of Low- to Middle-Income Countries 4 1.4 Definition of Burden of Disease 5 1.5 Definition of Disease Elimination 7 1.6 Definition of Disease Eradication 7 1.7 Definition of the Primary Point-of-Care 7 1.8 The 2000 Millennium Development Goals (MDGs) and Their Outcomes 7 1.9 Major Individual Diseases in the LMICs: The Big Three - Malaria, HIV/AIDS and Tuberculosis 9 1.10 Other Important Communicable Diseases in the LMICs 17 1.11 Neglected Tropical Disease (NTDs) Prioritized by the World Health Organisation 29 1.12 A Comparison of Health Metrics in an LMIC (Papua New Guinea) and a Developed Country (Australia) with a 7 km Distance Between them 31 1.13 Conclusions 32 Bibliography 32 Webliography 35 2 The Burden of Non-communicable Diseases in Low- and Middle-Income Countries 37Heiner Grosskurth 2.1 Introduction 38 2.2 Common Non-communicable Diseases in Low- and Middle-Income Countries 38 2.3 NCD Epidemiology 38 2.4 Prevention of Non-communicable Diseases 44 2.5 The Relationship Between Communicable and Non-communicable Diseases 44 2.6 The Health System Burden of NCDs 46 2.7 The Economic Impact of NCDs 47 2.8 The Response to the NCD Epidemic in LMICs 48 2.9 The Readiness of Primary Healthcare Services in LMICs to Cope with the NCD Burden 50 2.10 Introducing Effective NCD Control at Primary Care Services: A Practical Approach 52 2.11 The Role of Primary Healthcare Services in Cancer Prevention and Care 67 2.12 Evaluating Programmes to Strengthen NCD Services at Primary Care Level 70 2.13 Conclusions 70 Bibliography 70 Webliography 78 Part II How to improve healthcare in low- and middle-income countries by primary point-of-care rapid diagnostic testing 81 3 The Optimal Features of a Rapid Point-of-Care Diagnostic Test 83David Mabey and Rosanna Peeling 3.1 Introduction 83 3.2 Accuracy Versus Accessibility 83 3.3 Quality Assurance 84 3.4 The Importance of Connectivity 85 3.5 Environmental Friendliness 86 References 86 Webliography 87 4 Revolutionizing HIV Healthcare Delivery Through Rapid and Point-of-Care Testing 88Catherine J. Wedderburn, Debrah I. Boeras, and Rosanna W. Peeling 4.1 Synopsis 88 4.2 Introduction 89 4.3 Diagnostic Tests in Resource-Limited Settings 89 4.4 Challenges of Using Rapid and Point-of-Care Testing Within the Context of the Healthcare System 92 4.5 Recent Advances in HIV Diagnosis and Monitoring and Their Impact 93 4.6 WHO Recommendations: POC Diagnostics for Achieving the 90-90-90 Goals 98 4.7 Remaining Challenges - Human Resources, Quality Assurance, and Test Selection and Placement 98 4.8 Moving Forward 99 4.9 Conclusions 100 Bibliography 101 Webliography 103 5 Rapid Point-of-Care Diagnostic Tests for Tuberculosis 105Richard Lessells 5.1 Introduction 105 5.2 The Need for Rapid Point-of-Care TB Diagnostic Tests 106 5.3 Weaknesses in the TB Diagnostic Cascade 106 5.4 Potential Impact of Rapid Point-of-Care Diagnostic Tests 107 5.5 Defining the Diagnostic Needs 107 5.6 Smear Microscopy 107 5.7 Molecular Diagnostic Tests 109 5.8 Loop-Mediated Isothermal Amplification (LAMP) 112 5.9 Line Probe Assays 113 5.10 Other Molecular Tests 113 5.11 Antigen Tests 114 5.12 Combination Diagnostic Packages 115 5.13 Next Generation Sequencing 117 5.14 Diagnostic Imaging 117 5.15 Other Diagnostics 118 5.16 Conclusions 118 References 119 6 Rapid Diagnostic Tests for Syphilis 126David Mabey, Michael Marks, and Rosanna W. Peeling 6.1 Introduction 126 6.2 The Diagnosis of Syphilis 129 6.3 The Impact of POC Testing for Syphilis 131 6.4 Challenges in the Implementation of POC Testing 133 6.5 The Future 134 References 134 7 Point-of-Care and Near-Point-of-Care Diagnostic Tests for Malaria: Light Microscopy, Rapid Antigen-Detecting Tests and Nucleic Acid Amplification Assays 137Heidi Hopkins, and Jane Cunningham 7.1 Introduction 137 7.2 Diagnosis of Malaria 138 7.3 Light Microscopy of Blood Smears 139 7.4 Rapid Diagnostic Tests for Malaria (mRDTs) 140 7.5 Nucleic Acid Amplification-Based Tests (NAATs) for Malaria 142 7.6 Impact of Point-of-Care Testing for Malaria 143 7.7 Challenges in Implementation of POC Testing for Malaria 144 7.8 The Future 146 Biblography 146 Webliography 156 8 Rapid Diagnostic Tests for Human African Trypanosomiasis 159Veerle Lejon, Epco Hasker, and Philippe Buscher 8.1 Introduction 159 8.2 The Early Introduction of Immunodiagnostic Tests in the Diagnosis of HAT 160 8.3 CATT/T.b. gambiense: A Breakthrough in the Immunodiagnosis of Gambiense-HAT 161 8.4 The Changing Epidemiology of Gambiense-HAT: The Need for Improved Rapid Diagnostic Tests 163 8.5 Second Generation RDTs for HAT 165 8.6 Future Perspectives and Challenges 165 References 166 Webliography 169 9 Rapid Diagnostic Tests for Visceral Leishmaniasis 170Marleen Boelaert, Suman Rijal, and Francois Chappuis 9.1 Introduction 170 9.2 Parasitology, a Reference Standard? 171 9.3 Serological Assays 172 9.4 The First Serological Test for Field Use: The Direct Agglutination Assay 173 9.5 The Early Development an Immunochromatographic Test Using the Recombinant Leishmania Antigen rK39 174 9.6 Impact of the VL RDT 174 9.7 Challenges 175 9.8 Other Tests 175 9.9 Discussion 176 9.10 Conclusions 177 References 177 10 A Rapid Diagnostic Test for Dengue 181Claire Mullender, and James Whitehorn 10.1 Introduction 181 10.2 Clinical Features of Dengue 182 10.3 The Importance of Making a Rapid Diagnosis 183 10.4 The Host Response to Infection 184 10.5 Existing Diagnostic Strategies 184 10.6 Review of Existing Rapid Diagnostic Tests 186 10.7 Future Directions 188 10.8 Conclusions 188 References 188 11 Rapid Diagnostic Tests for Influenza 191A.C. Hurt, and I.G. Barr 11.1 Introduction 191 11.2 Overview of RIDTs 192 11.3 Antigen Detection-based RIDTs 195 11.4 Nucleic Acid Detection-based RIDTs 197 11.5 Factors that Alter RIDTs Performance 198 11.6 The Use of RIDTs in LMICs 198 11.7 Conclusions 199 Acknowledgment 199 References 200 12 A Rapid Diagnostic Test for Ebola Virus Disease 202Catherine Houlihan and Colin Brown 12.1 Case Report 202 12.2 Introduction 203 12.3 Diagnostic Methods to Detect Ebola Virus Disease 203 12.4 Rapid Diagnostic Tests for Ebola Virus Disease for Use in a Point-of-Care Facility 206 12.5 Conclusions 209 Bibliography 210 Webliography 212 13 Rapid Diagnostic Tests for Yaws 213Michael Marks 13.1 Introduction 213 13.2 Epidemiology 214 13.3 Clinical Features 215 13.4 Diagnostic Quandaries 217 13.5 Diagnostic Tests for Yaws 217 13.6 Rapid Diagnostic Tests for Yaws 218 13.7 Molecular Assays 219 References 221 14 Rapid Diagnostic Tests for the Detection of Sickling Hemoglobin 224Amina Nardo-Marino and Tom N. Williams 14.1 Sickle Cell Disease 224 14.2 Diagnosing Sickle Cell Disease 225 14.3 Conclusions 229 Bibliography 229 15 Progress Toward the Development of Rapid Diagnostic Tests for Lymphatic Filariasis and Onchocerciasis 231Roger B. Peck, Dunia Faulx, and Tala de los Santos 15.1 Introduction 231 15.2 The Development of Rapid Diagnostic Tests 234 15.3 Rapid Diagnostic Tests for Lymphatic Filariasis 234 15.4 Rapid Diagnostic Tests for Onchocerciasis 236 15.5 Next tests and Steps 240 Bibliography 240 Webliography 242 Part III Other tests that can be performed rapidly at the primary-point-of-care 245 16 Point-of-Care Testing for Blood Counts, HbA1c, Renal Function, Electrolytes, Acid-Base Balance and Hepatitis 247Mark Shephard, Lara Motta, Brooke Spaeth, Heather Halls, and Lauren Duckworth 16.1 Introduction 248 16.2 Point-of-Care Testing for Blood Counts 248 16.3 Point-of-Care Testing for HbA1c 252 16.4 Point-of-Care Testing for Renal Function 254 16.5 Point-of-Care Testing for Electrolytes and Acid-Base Balance 257 16.6 Point-of-Care Testing for Hepatitis 261 16.7 Conclusions 265 Bibliography 266 Webliography 268 17 Microscopy Skills: Cell Counts, Gram Stains, Ziehl-Neelsen Staining (ZN) and Blood Films 270Michael Harrison 17.1 Introduction 270 17.2 Microscopy 271 17.3 Microscopy in a POC Testing Laboratory 273 17.4 Gram Staining 274 17.5 Ziehl-Neelsen Stain (ZN) for Mycobacterium tuberculosis 275 17.6 Blood Film Preparation, Staining and Reporting 276 17.7 Conclusions 278 Bibliography 280 Webliography 280 18 India Ink Stain and Cryptococcal Antigen Test for Cryptococcal Infection 281Hannah K. Mitchell, Joseph N. Jarvis, and Mark W. Tenforde 18.1 Introduction 281 18.2 Diagnosis of Cryptococcal Meningitis 282 18.3 Cryptococcal Antigen Testing (CrAg) 283 18.4 India Ink Stain 285 18.5 CrAg Testing for the Prevention of Cryptococcal Meningitis 286 18.6 Logistical Challenges of CrAg Screening 288 18.7 Non-Meningeal Cryptococcal Disease 289 18.8 Conclusions 289 References 290 19 Mid Upper Arm Circumference Tapes for Assessment of Severe Acute Malnutrition 294Jane Crawley, Martha Mwangome, James Berkley, and Andre Briend 19.1 Introduction 294 19.2 Mid Upper Arm Circumference (MUAC) 296 19.3 Comparison of MUAC with other Anthropometric Indices 296 19.4 MUAC: A Brief Historical Perspective 296 19.5 Technique for Measuring MUAC 297 19.6 MUAC, Mortality Risk, and Definitions of Severe Acute Malnutrition 298 19.7 Conclusions: Use of MUAC in Different Settings 301 References 302 Webliography 304 20 Spirometry for Chronic Obstructive Pulmonary Disease Due to Inhalation of Smoke from Indoor Fires Used for Cooking and Heating 306Janet G. Shaw, Annalicia Vaughan, Emma Smith, Cai Fong, Svetlana Stevanovic, and Ian A. Yang 20.1 Introduction 306 20.2 Indoor Air Pollution from Burning Biomass 307 20.3 Mechanisms of Lung Damage from Exposure to Biomass Smoke 309 20.4 Biomass Smoke-Related Chronic Obstructive Pulmonary Disease (COPD) 311 20.5 Detecting Airflow Obstruction in Biomass Smoke-Related COPD 314 20.6 Lessons Learnt from Clinical Guidelines for the Detection of Cigarette Smoking-Related COPD 317 20.7 Conclusions 319 Acknowledgments 320 Bibliography 320 Webliography 326 21 Point-of-Care Pulse Oximetry for Children in Low-Resource Settings 327Carina King, Hamish Graham, and Eric D. McCollum 21.1 Introduction 327 21.2 Hypoxemia 328 21.3 Pulse Oximetry 330 21.4 Current Situation in Low-Resource Settings 332 21.5 Current Challenges and Future Opportunities 333 21.6 Conclusions 339 Acknowledgments 339 Bibliography 340 Webliography 343 22 The Use of Near-Infrared Spectroscopy to Monitor Tissue Oxygenation, Metabolism and Injury in Low Resource Settings 344Gemma Bale, and Ilias Tachtsidis 22.1 Introduction 344 22.2 Near-Infrared Spectroscopy 346 22.3 Clinical Applications 349 22.4 Research Applications 350 22.5 The Use of NIRS in Low Resource Settings 350 22.6 Conclusions 355 Bibliography 356 Webliography 357 Part IV Cheap imaging technologies 361 23 The Use of Point-of-Care Ultrasound in the Resource-Limited Setting 363Tom Heller, Michaela A.M. Huson, Sabine Belard, Dan Kaminstein, and Elizabeth Joekes 23.1 Introduction to Point-of-Care Ultrasound (POCUS) 365 23.2 Physics and Technical Aspects of Ultrasound 366 23.3 Most Relevant POCUS Applications in the Resource-Limited Setting 369 23.4 Considerations for Teaching and Implementation 402 23.5 Conclusions 403 Bibliography 403 Webliography 405 24 The Use of Obstetric Ultrasound in Low Resource Settings 406Helen Allott 24.1 Introduction 406 24.2 Pregnancy-Related Problems for Which Portable Ultrasound may be Useful 406 24.3 Problems with the Use of Ultrasound Scanning in Limited Resource Settings 407 24.4 Provision of Trained Sonographers 409 24.5 The Perspective of the Pregnant Woman to Antenatal Ultrasound Scanning 410 24.6 Abuse of Ultrasound Scanning in Pregnancy 410 24.7 Advances in Ultrasound Technology (and See Chapter 23) 411 24.8 Targeted Ultrasound Scanning 412 24.9 Conclusions 412 References 413 25 Examining the Optic Fundus and Assessing Visual Acuity and Visual Fields Using Mobile Technology 414Nigel M. Bolster, and Andrew Bastawrous 25.1 Introduction: The Ascent of Mobile Technology 414 25.2 Visual Acuity 418 25.3 Visual Fields 424 25.4 Smartphone Ophthalmoscopy 427 25.5 Discussion 432 25.6 Conclusions 434 Part V Telemedicine 439 26 Telemedicine for Clinical Management of Adults in Remote and Rural Areas 441Farhad Fatehi, Monica Taylor, Liam J. Caffery, and Anthony C. Smith 26.1 Introduction 442 26.2 Definitions 443 26.3 Types of Service 444 26.4 Purposes of Telemedicine 444 26.5 Telemedicine for Improving Access to Care 445 26.6 Establishing a Sustainable Telehealth Network: A Case Study from Brazil 445 26.7 Swinfen Telemedicine: A Case Study of Intercontinental Telemedicine 446 26.8 Telemedicine in Natural Disaster Responses 446 26.9 Telemedicine for Remote Training of Healthcare Professionals 447 26.10 Telemedicine for Mental Health (and see Chapter 29) 449 26.11 The Rise of Mobile Health (mHealth) 451 26.12 Social Networking for Clinical Purposes 452 26.13 The World Health Organization and Telemedicine 456 26.14 Challenges and Barriers to Implementation 457 26.15 Conclusions 459 Bibliography 460 Webliography 461 27 Telemedicine for the Delivery of Specialist Pediatric Services 462Anthony C. Smith, Monica Taylor, Farhad Fatehi, and Liam J. Caffery 27.1 Introduction 463 27.2 Technical Consideration for Telemedicine in LMICs 464 27.3 Models of Care in Telepediatrics 469 27.4 Swinfen Charitable Trust Telemedicine Service 469 27.5 Selected Examples of SCT Referrals 470 27.6 National and International Telemedicine Services 474 27.7 mHealth Applications for LMICs 475 27.8 Telemedicine Screening Services 476 27.9 Telemedicine Support during Disaster Situations 476 27.10 Challenges Associated with Telemedicine Adoption in LMICs 477 27.11 Telepediatric Case Studies in LMICs 478 27.12 Pathology Services 480 27.13 Radiographic (Imaging) Services 480 27.14 Maternal Health Services 481 27.15 Conclusions 481 27.16 Acknowledgements 481 27.17 Useful Websites 481 Bibliography 482 Webliography 486 28 Telemedicine in the Diagnosis and Management of Skin Diseases 488Giselle Prado, Odinaka Anyanwu, and Carrie Kovarik 28.1 Introduction 489 28.2 Methods of Delivering Teledermatology: Store and Forward Versus Live Interactive Methods 490 28.3 The History of Teledermatology 490 28.4 Global Teledermatology Programs 490 28.5 Teledermatology in Africa 491 28.6 BUP: The Botswana - University of Pennsylvania Partnership 493 28.7 Teledermatopathology in Botswana 494 28.8 Diagnostic Concordance 495 28.9 Teledermatology in Asia 497 28.10 Teledermatology in Latin America 497 28.11 Barriers 498 28.12 Costs 499 28.13 Education and Training 499 28.14 Equipment and Internet Access 499 28.15 Privacy Concerns 500 28.16 Cultural Hesitancy 500 28.17 Language Barriers 501 28.18 Availability of Treatments 501 28.19 Legal Issues 501 28.20 Follow-up 501 28.21 Ensuring Success of a New Teledermatology Initiative 501 28.22 Conclusions 502 Bibliography 502 29 Digital Technology, Including Telemedicine, in the Management of Mental Illness 505John A Naslund, Sophia M. Bartels, and Lisa A. Marsch 29.1 Introduction and Background 505 29.2 Why Mental Disorders? 506 29.3 Growing Access to Digital Technology and New Opportunities 508 29.4 Promising Examples from Low- and Middle-Income Countries 509 29.5 Critical Assessment of the Risks and Limitations 517 29.6 Future Directions and Implications 519 29.7 Conclusions 524 Bibliography 525 Webliography 530 30 The Use of Mobile Chest X-Rays for Tuberculosis Telemedicine 531Meghan L. Jardon, Kelsey L. Pomykala, Ishita Desai, and Kara-Lee Pool 30.1 Background 531 30.2 Lack of Access to Radiology 532 30.3 Implementation 532 30.4 Cost 536 30.5 Sustainability 536 30.6 Chest X-Ray Information Technology (IT) 538 30.7 Mobile Devices 540 30.8 Education to Ensure Sustainability 541 30.9 Conclusions 542 Bibliography 542 Webliography 545 Part VI The future 549 31 An Introduction to Digital Health 551Kerry Atkinson 31.1 Introduction 552 31.2 The Pillars and Components of Digital Health for Use in the LMICs 552 31.3 Smartphones and Internet Access 554 31.4 Wearables 555 31.5 Personal Digital Assistants and Chatbots 558 31.6 Augmented Reality 558 31.7 Big Data 558 31.8 Artificial Intelligence (AI) 558 31.9 The Game Changer - A Smartphone with AI Access 563 31.10 Conclusions 564 Bibliography 564 Webliography 564 32 Digital Health in Low- and Middle-Income Countries 566Martin Seneviratne and David Peiris 32.1 Introduction - The Digital Health Revolution 567 32.2 The Current Landscape 569 32.3 HIV/AIDS 569 32.4 Diabetes Mellitus 570 32.5 Maternal Health 570 32.6 Core Functionalities 571 32.7 Patient-facing Functions 571 32.8 Clinician-facing Functions 573 32.9 Electronic Medical Record Management 574 32.10 Point-of-Care Diagnostic Tests 575 32.11 Epidemiology 575 32.12 Inventory Management and Supply Chain 575 32.13 Challenges to Scale 575 32.14 Emerging Trends and Future Vision 578 32.15 Conclusions 580 Bibliography 580 Webliography 583 33 Nucleic Acid Detection of Tuberculosis Via Innovative Point-of-Care Nanotechnologies Targeted for Low Resource Settings 584Benjamin Y.C. Ng, Eugene J.H. Wee, Nicholas P. West, and Matt Trau 33.1 Introduction 584 33.2 Nucleic Acid Detection of Tuberculosis 585 33.3 The Availability of Rapid Diagnostic Tests at the Peripheral Healthcare Level 585 33.4 Leveraging Innovative Nanotechnologies for Point-of-Care TB Diagnosis 587 33.5 Sample Preparation Workflow 589 33.6 Nanotechnologies for TB DNA Sensing and Readouts 590 33.7 Quantitative DNA Detection Methodologies 592 33.8 Drug-resistant Tuberculosis 594 33.9 Conclusions 595 References 596 34 The Use of Functional Nanoparticles for Water Purification 600Jing Zhang, Chuanping Feng, and Chengzhong Yu 34.1 Introduction 600 34.2 Disinfection 602 34.3 Adsorption 607 34.4 Electrochemistry 609 34.5 Conclusions and Future Perspectives 609 References 610 35 The Use of Drones in the Delivery of Rural Healthcare 615Debrah I. Boeras, Blanche C. Collins, and Rosanna W. Peeling 35.1 Challenges in Healthcare Delivery - Opportunities for Innovation 616 35.2 The Need for Disruptive Solutions for Healthcare Delivery in Rural Areas 616 35.3 The Use of Drones for Healthcare Delivery 617 35.4 Further Focus on Uptake of Drone Technology by Different Countries 621 35.5 Models of Potential Public-Private Collaboration 622 35.6 Promises and Challenges of the Use of Drones in Healthcare Delivery 623 35.7 Outlook for the Future 624 35.8 Conclusions 626 Bibliography 626 Webliography 630 36 Implementation of Point-of-Care Tests: Lessons Learnt 633Rosanna W. Peeling, and Debrah I. Boeras 36.1 Synopsis 633 36.2 Healthcare Needs in Low- and Middle-Income Countries 634 36.3 Rapid Diagnostic Tests for Human Immunodeficiency Virus (HIV) Disease (and See Chapter 4) 636 36.4 Rapid Diagnostic Tests for Syphilis (and See Chapter 6) 637 36.5 Rapid Diagnostic Tests for Tuberculosis (TB) (and See Chapter 5) 638 36.6 Rapid Diagnostic Tests for Malaria (and See Chapter 7) 638 36.7 Lessons Learnt from the Implementation of POC Tests 639 36.8 Lessons Learnt from the Implementation of POC Tests for Three Diseases 640 36.9 The Way Forward 642 36.10 The New Paradigm for Technological Innovation and Implementation 643 36.11 Conclusions 644 Bibliography 644 Webliography 648 37 Useful Electronic Healthcare Resources Available for Those Working in Remote Settings 649Tyler Evans 37.1 Introduction 649 37.2 General Web-Based Resources 650 37.3 Travel Medicine 651 37.4 The Big Three Communicable Diseases in Low- and Middle-Income Countries (LMICs) 652 37.5 Hepatitis C 656 37.6 Other Infectious Diseases (IDs) 657 37.7 Dermatology 657 37.8 Obstetrics and Gynecology 658 37.9 Pediatrics 658 37.10 Psychiatry 658 37.11 Emergency Medicine (EM) 659 37.12 Preventive Health 659 37.13 Disease Mapping 660 37.14 Pharmaceuticals 660 37.15 Online Courses 661 37.16 Recommended Books 661 37.17 Institutions, Societies and Books 662 Webliography 663 38 The Future - How Do We Get from Here to There? 666Kerry Atkinson and David Mabey 38.1 Progress to Date 667 38.2 Major Factors Adversely Affecting Global Health 670 38.3 Continue Doing What Works 674 38.4 New Measures for Improving Remote Rural Healthcare 674 38.5 The UN 2015 Sustainable Development Goals for 2016-2030 677 38.6 Conclusions 681 Bibliography 682 Webliography 683 Glossary 684 Index 693

Citation preview

Revolutionizing Tropical Medicine

Revolutionizing Tropical Medicine Point‐of‐Care Tests, New Imaging Technologies and Digital Health

Edited by

Kerry Atkinson

University of Queensland Centre for Clinical Research, Brisbane, Australia and the University of Technology/ Institute of Health and Biomedical Innovation, Brisbane, Australia

David Mabey

London School of Hygiene and Tropical Medicine, London, UK

This edition first published 2019 © 2019 John Wiley & Sons, Inc All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, except as permitted by law. Advice on how to obtain permission to reuse material from this title is available at http://www.wiley.com/go/permissions. The right of Kerry Atkinson and David Mabey to be identified as the authors of the editorial material in this work has been asserted in accordance with law. Registered Office(s) John Wiley & Sons, Inc., 111 River Street, Hoboken, NJ 07030, USA Editorial Office The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, UK For details of our global editorial offices, customer services, and more information about Wiley products visit us at www.wiley.com. Wiley also publishes its books in a variety of electronic formats and by print‐on‐demand. Some content that appears in standard print versions of this book may not be available in other formats. Limit of Liability/Disclaimer of Warranty While the publisher and authors have used their best efforts in preparing this work, they make no representations or warranties with respect to the accuracy or completeness of the contents of this work and specifically disclaim all warranties, including without limitation any implied warranties of merchantability or fitness for a particular purpose. No warranty may be created or extended by sales representatives, written sales materials or promotional statements for this work. The fact that an organization, website, or product is referred to in this work as a citation and/or potential source of further information does not mean that the publisher and authors endorse the information or services the organization, website, or product may provide or recommendations it may make. This work is sold with the understanding that the publisher is not engaged in rendering professional services. The advice and strategies contained herein may not be suitable for your situation. You should consult with a specialist where appropriate. Further, readers should be aware that websites listed in this work may have changed or disappeared between when this work was written and when it is read. Neither the publisher nor authors shall be liable for any loss of profit or any other commercial damages, including but not limited to special, incidental, consequential, or other damages. Library of Congress Cataloging‐in‐Publication Data has been applied for: ISBN: 9781119282648 (Hardback)

Cover Design: Wiley Cover Images: © notbad/Shutterstock, © piick/Shutterstock, © Wikimedia Commons Set in 10/12pt WarnockPro by SPi Global, Chennai, India

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“The wounded surgeon plies the steel That questions the distempered part; Beneath the bleeding hands we feel The sharp compassion of the healer’s art Resolving the enigma of the fever chart.” Four Quartets. IV. East Coker T.S. Eliot, Nobel Laureate in Literature, 1948.

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Contents Editor’s Preface  xxix List of Contributors  xxxi Part I The Health of Low‐ and Middle‐Income Countries Today  1

1

The Burden of Communicable Diseases in Low‐ and  Middle‐Income Countries  3 Kerry Atkinson and David Mabey

1.1 Introduction  4 1.2 Definition of a Communicable Disease  4 1.3 Definition of Low‐ to Middle‐Income Countries  4 1.4 Definition of Burden of Disease  5 1.4.1 Disability‐Adjusted Life Years  5 1.5 Definition of Disease Elimination  7 1.6 Definition of Disease Eradication  7 1.7 Definition of the Primary Point‐of‐Care  7 1.8 The 2000 Millennium Development Goals (MDGs) and Their Outcomes  7 1.9 Major Individual Diseases in the LMICs: The Big Three ‐ Malaria, HIV/AIDS and Tuberculosis  9 1.9.1 Malaria  9 1.9.2 HIV/AIDS  10 1.9.3 Tuberculosis (TB)  11 1.9.3.1 Multidrug‐Resistant Tuberculosis  15 1.9.3.2 Extensively Drug‐Resistant TB (XDR‐TB)  17 1.9.3.3 The Co‐epidemics of TB and HIV/AIDS  17 1.10 Other Important Communicable Diseases in the LMICs  17 1.10.1 Lower Respiratory Tract Infections  24 1.10.1.1 WHO 24 1.10.1.2 Data Sources and Analysis  24 1.10.1.3 Global Burden of Disease Collaborators, 2016  27 1.10.2 Diarrheal Diseases  28 1.10.3 Meningitis  28 1.10.4 Sexually Transmitted Diseases (Excluding HIV/AIDS)  28 1.10.5 Hepatitis  28 1.10.6 Measles  28

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Contents

1.10.7 Whooping Cough (Pertussis)  28 1.10.8 Tetanus  29 1.10.9 Yellow Fever  29 1.11 Neglected Tropical Disease (NTDs) Prioritized by the World Health Organisation  29 1.12 A Comparison of Health Metrics in an LMIC (Papua New Guinea) and a Developed Country (Australia) with a 7 km Distance Between them  31 1.13 Conclusions  32 Bibliography  32 Webliography  35 2

The Burden of Non‐communicable Diseases in Low‐ and Middle‐Income Countries  37 Heiner Grosskurth

2.1 Introduction  38 2.2 Common Non‐communicable Diseases in Low- and Middle-Income Countries  38 2.3 NCD Epidemiology  38 2.3.1 Arterial Hypertension and Cardiovascular Diseases  39 2.3.2 Diabetes Mellitus  40 2.3.3 The Metabolic Syndrome  41 2.3.4 Chronic Kidney Disease  41 2.3.5 Chronic Obstructive Pulmonary Disease (COPD)  41 2.3.6 Asthma  42 2.3.7 Cancer  43 2.4 Prevention of Non‐communicable Diseases  44 2.5 The Relationship Between Communicable and Non‐communicable Diseases  44 2.6 The Health System Burden of NCDs  46 2.7 The Economic Impact of NCDs  47 2.7.1 The Patient’s Perspective  47 2.7.2 The Provider’s Perspective  47 2.7.3 Macroeconomic Effects  48 2.8 The Response to the NCD Epidemic in LMICs  48 2.8.1 Response at the International Level  48 2.8.2 Response at the National Level  49 2.8.3 Response by the Private Sector  50 2.9 The Readiness of Primary Healthcare Services in LMICs to Cope with the NCD Burden  50 2.10 Introducing Effective NCD Control at Primary Care Services: A Practical Approach  52 2.10.1 Raising NCD Awareness Within the Health Services  52 2.10.2 Training Healthcare Workers  52 2.10.3 Conducting Support Supervision  53 2.10.4 Providing Essential Diagnostic Equipment and Tests  64 2.10.5 Ensuring a Reliable Supply of Essential NCD Drugs  64 2.10.6 Introducing Standardized NCD Case Management Algorithms  65

Contents

2.10.7

Treating Patients Close to Their Residence: Effective Referral and Back‐referral  65 2.10.8 Introducing Health Education and NCD Case Detection  66 2.10.9 Establishing an Effective Recording System  67 2.10.10 Integrating NCD Control Measures into Outreach Activities  67 2.11 The Role of Primary Healthcare Services in Cancer Prevention and Care  67 2.12 Evaluating Programmes to Strengthen NCD Services at Primary Care Level  70 2.13 Conclusions  70 Bibliography  70 Webliography  78 Part II 

3

 ow to improve healthcare in low‐ and middle‐income countries H by primary point‐of‐care rapid diagnostic testing  81

The Optimal Features of a Rapid Point-of-Care Diagnostic Test  83 David Mabey and Rosanna Peeling  83

3.1 Introduction  83 3.2 Accuracy Versus Accessibility  83 3.3 Quality Assurance  84 3.4 The Importance of Connectivity  85 3.5 Environmental Friendliness  86 References  86 Webliography  87 4

Revolutionizing HIV Healthcare Delivery Through Rapid and Point‐of‐Care Testing  88 Catherine J. Wedderburn, Debrah I. Boeras, and Rosanna W. Peeling

4.1 Synopsis  88 4.2 Introduction  89 4.3 Diagnostic Tests in Resource‐Limited Settings  89 4.3.1 Challenges of Healthcare Delivery in Resource‐Limited Settings  89 4.3.2 Diagnostic Tests Needed to Reach the 90‐90‐90 Targets  90 4.3.2.1 The First 90  90 4.3.2.2 The Second 90  92 4.3.2.3 The Third 90  92 4.4 Challenges of Using Rapid and Point‐of‐Care Testing Within the Context of the Healthcare System  92 4.5 Recent Advances in HIV Diagnosis and Monitoring and Their Impact  93 4.5.1 HIV Self‐Testing and Multiplex Testing  93 4.5.2 Early Infant Diagnosis of HIV  94 4.5.3 POC CD4 Testing for Managing HIV Patient Care  96 4.5.3.1 Before the Initiation of ART  96 4.5.3.2 The Use of the CD4 Test for Early HIV Disease  96 4.5.3.3 The CD4 Test for Advanced HIV Disease  97 4.5.4 POC HIV Viral Load Monitoring  97

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Contents

4.6

WHO Recommendations: POC Diagnostics for Achieving the 90‐90‐90 Goals  98 4.7 Remaining Challenges – Human Resources, Quality Assurance, and Test Selection and Placement  98 4.8 Moving Forward  99 4.9 Conclusions  100 Bibliography  101 Webliography  103 5

Rapid Point‐of‐Care Diagnostic Tests for Tuberculosis  105 Richard Lessells

5.1 Introduction  105 5.2 The Need for Rapid Point‐of‐Care TB Diagnostic Tests  106 5.2.1 The Diagnostic Gap  106 5.3 Weaknesses in the TB Diagnostic Cascade  106 5.4 Potential Impact of Rapid Point‐of‐Care Diagnostic Tests  107 5.5 Defining the Diagnostic Needs  107 5.6 Smear Microscopy  107 5.6.1 Improving the Performance of Smear Microscopy  108 5.6.2 Point‐of‐Care Smear Microscopy  108 5.7 Molecular Diagnostic Tests  109 5.7.1 Xpert MTB/RIF  109 5.7.2 Point‐of‐Care Testing with Xpert  110 5.7.3 Impact of Xpert for Drug‐Resistant TB  111 5.7.4 New Developments with Xpert MTB/RIF  111 5.8 Loop‐Mediated Isothermal Amplification (LAMP)  112 5.9 Line Probe Assays  113 5.10 Other Molecular Tests  113 5.11 Antigen Tests  114 5.11.1 Urine Lipoarabinomannan Assay  114 5.12 Combination Diagnostic Packages  115 5.13 Next Generation Sequencing  117 5.14 Diagnostic Imaging  117 5.15 Other Diagnostics  118 5.16 Conclusions  118 ­References  119 6

Rapid Diagnostic Tests for Syphilis  126 David Mabey, Michael Marks, and Rosanna W. Peeling

6.1 Introduction  126 6.2 The Diagnosis of Syphilis  129 6.2.1 Laboratory Based Tests  129 6.2.2 Point‐of‐Care Tests  129 6.3 The Impact of POC Testing for Syphilis  131 6.4 Challenges in the Implementation of POC Testing  133 6.4.1 Training and Logistics  133 6.4.2 Quality Assurance  133

Contents

6.5 The Future  134 ­References  134 7

Point‐of‐Care and Near‐Point‐of‐Care Diagnostic Tests for Malaria: Light Microscopy, Rapid Antigen‐Detecting Tests and Nucleic Acid Amplification Assays  137 Heidi Hopkins, and Jane Cunningham

7.1 Introduction  137 7.2 Diagnosis of Malaria  138 7.3 Light Microscopy of Blood Smears  139 7.4 Rapid Diagnostic Tests for Malaria (mRDTs)  140 7.5 Nucleic Acid Amplification‐Based Tests (NAATs) for Malaria  142 7.6 Impact of Point‐of‐Care Testing for Malaria  143 7.7 Challenges in Implementation of POC Testing for Malaria  144 7.7.1 Training and Logistics  144 7.7.2 Quality Assurance and Quality Control (QA/QC)  144 7.7.3 Special Populations  145 7.8 The Future  146 Biblography  146 Webliography  156 8

Rapid Diagnostic Tests for Human African Trypanosomiasis 159 Veerle Lejon, Epco Hasker, and Philippe Büscher

8.1 Introduction  159 8.2 The Early Introduction of Immunodiagnostic Tests in the Diagnosis of HAT  160 8.3 CATT/T.b. gambiense: A Breakthrough in the Immunodiagnosis of Gambiense‐HAT  161 8.4 The Changing Epidemiology of Gambiense‐HAT: The Need for Improved Rapid Diagnostic Tests  163 8.5 Second Generation RDTs for HAT  165 8.6 Future Perspectives and Challenges  165 References  166 Webliography  169 9

Rapid Diagnostic Tests for Visceral Leishmaniasis  170 Marleen Boelaert, Suman Rijal, and François Chappuis

9.1 Introduction  170 9.2 Parasitology, a Reference Standard?  171 9.3 Serological Assays  172 9.4 The First Serological Test for Field Use: The Direct Agglutination Assay  173 9.5 The Early Development an Immunochromatographic Test Using the Recombinant Leishmania Antigen rK39  174 9.6 Impact of the VL RDT  174 9.7 Challenges  175 9.8 Other Tests  175

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9.9 Discussion  176 9.10 Conclusions  177 ­References  177 10

A Rapid Diagnostic Test for Dengue  181 Claire Mullender, and James Whitehorn

10.1 Introduction  181 10.2 Clinical Features of Dengue  182 10.3 The Importance of Making a Rapid Diagnosis  183 10.4 The Host Response to Infection  184 10.5 Existing Diagnostic Strategies  184 10.6 Review of Existing Rapid Diagnostic Tests  186 10.7 Future Directions  188 10.8 Conclusions  188 ­References  188 11

Rapid Diagnostic Tests for Influenza  191 A.C. Hurt, and I.G. Barr

11.1 Introduction  191 11.2 Overview of RIDTs  192 11.3 Antigen Detection‐based RIDTs  195 11.4 Nucleic Acid Detection‐based RIDTs  197 11.5 Factors that Alter RIDTs Performance  198 11.6 The Use of RIDTs in LMICs  198 11.7 Conclusions  199 ­ Acknowledgment  199 ­References  200 12

A Rapid Diagnostic Test for Ebola Virus Disease  202 Catherine Houlihan and Colin Brown

12.1 Case Report  202 12.2 Introduction  203 12.3 Diagnostic Methods to Detect Ebola Virus Disease  203 12.4 Rapid Diagnostic Tests for Ebola Virus Disease for Use in a Point‐of‐Care Facility  206 12.5 Conclusions  209 Bibliography  210 Webliography  212 13

Rapid Diagnostic Tests for Yaws  213 Michael Marks

13.1 Introduction  213 13.2 Epidemiology  214 13.3 Clinical Features  215 13.3.1 Primary Yaws  215 13.3.2 Secondary Yaws  215 13.3.3 Tertiary Yaws  217 13.4 Diagnostic Quandaries  217

Contents

13.5 Diagnostic Tests for Yaws  217 13.5.1 Serology  217 13.6 Rapid Diagnostic Tests for Yaws  218 13.6.1 The DPP Syphilis Screen and Confirm Kit  218 13.6.2 Luminex  219 13.7 Molecular Assays  219 ­References  221 14

Rapid Diagnostic Tests for the Detection of Sickling Hemoglobin  224 Amina Nardo‐Marino and Tom N. Williams

14.1 Sickle Cell Disease  224 14.2 Diagnosing Sickle Cell Disease  225 14.2.1 The Blood Film  225 14.2.2 The Sodium Metabisulfite Sickling Test  226 14.2.3 The Sickle Solubility Test (SICKLEDEX)  227 14.2.4 Novel Point‐of‐Care Tests  228 14.3 Conclusions  229 ­Bibliography  229 15

Progress Toward the Development of Rapid Diagnostic Tests for Lymphatic Filariasis and Onchocerciasis  231 Roger B. Peck, Dunia Faulx, and Tala de los Santos

15.1 Introduction  231 15.2 The Development of Rapid Diagnostic Tests  234 15.3 Rapid Diagnostic Tests for Lymphatic Filariasis  234 15.3.1 Antigen Detection  234 15.3.2 Antibody Detection  235 15.4 Rapid Diagnostic Tests for Onchocerciasis  236 15.4.1 Antigen Detection  236 15.4.2 Antibody Detection  238 15.5 Next tests and Steps  240 Bibliography  240 Webliography  242 Part III 

16

 ther tests that can be performed rapidly at the O primary‐point‐of-care  245

Point‐of‐Care Testing for Blood Counts, HbA1c, Renal Function, Electrolytes, Acid–Base Balance and Hepatitis  247 Mark Shephard, Lara Motta, Brooke Spaeth, Heather Halls, and Lauren Duckworth

16.1 Introduction  248 16.2 Point‐of‐Care Testing for Blood Counts  248 16.2.1 Clinical Use of Blood Counts  248 16.2.2 POC Testing Device Options for Hemoglobin Estimation  249 16.2.3 POC Testing Device Options for Full Blood Count Estimation  250 16.2.4 A Case Study Illustrating the Value of POC Testing for White Blood Cell Counts  251

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16.2.5 Presentation/History  251 16.2.6 Examinations  251 16.2.7 Treatment/Follow‐up  251 16.2.8 Outcome  251 16.2.9 Summary  252 16.3 Point‐of‐Care Testing for HbA1c  252 16.3.1 Clinical Use of Hemoglobin A1c  252 16.3.2 POC Testing Device Options for Measuring HbA1c  252 16.3.3 An Example of a POC Testing Model with Application in the LMICs  253 16.4 Point‐of‐Care Testing for Renal Function  254 16.4.1 Clinical Summary  254 16.4.2 POC Testing Device Options for Creatinine  255 16.4.3 POC Testing Device Options for Urine Albumin  256 16.4.4 A Case Study Illustrating the Value of POC Testing for Renal Function  256 16.4.4.1 Presentation 257 16.4.4.2 POC Testing Performed  257 16.4.4.3 Diagnosis 257 16.4.4.4 Treatment/Follow‐up 257 16.4.4.5 Outcome 257 16.4.4.6 Summary 257 16.5 Point‐of‐Care Testing for Electrolytes and Acid–Base Balance  257 16.5.1 Clinical Use of Tests for Electrolytes and Acid–Base Balance  257 16.5.2 POC Testing Device Options for Electrolyte Profile and Acid–Base Balance  259 16.6 Point‐of‐Care Testing for Hepatitis  261 16.6.1 Clinical Use of Hepatitis Testing  261 16.6.2 Pathology Tests for Hepatitis  262 16.6.3 POC Testing for Hepatitis B  262 16.6.4 POC Testing for Hepatitis C  263 16.7 Conclusions  265 Bibliography  266 Webliography  268 17

Microscopy Skills: Cell Counts, Gram Stains, Ziehl‐Neelsen Staining (ZN) and Blood Films  270 Michael Harrison

17.1 Introduction  270 17.2 Microscopy  271 17.3 Microscopy in a POC Testing Laboratory  273 17.4 Gram Staining  274 17.5 Ziehl‐Neelsen Stain (ZN) for Mycobacterium tuberculosis  275 17.6 Blood Film Preparation, Staining and Reporting  276 17.6.1 Manual Preparation of a Blood Film  276 17.6.2 Staining of the Blood Film  277 17.6.3 Alternative Diff‐Quick Method  277 17.7 Conclusions  278 Bibliography  280 Webliography  280

Contents

18

India Ink Stain and Cryptococcal Antigen Test for Cryptococcal Infection  281 Hannah K. Mitchell, Joseph N. Jarvis, and Mark W. Tenforde

18.1 Introduction  281 18.2 Diagnosis of Cryptococcal Meningitis  282 18.3 Cryptococcal Antigen Testing (CrAg)  283 18.3.1 Latex Agglutination (LA) and Enzyme‐Linked ImmunoSorbent Assays (ELISA)  283 18.3.2 Lateral Flow Assay  284 18.4 India Ink Stain  285 18.5 CrAg Testing for the Prevention of Cryptococcal Meningitis  286 18.6 Logistical Challenges of CrAg Screening  288 18.7 Non‐Meningeal Cryptococcal Disease  289 18.8 Conclusions  289 ­References  290 19

Mid Upper Arm Circumference Tapes for Assessment of Severe Acute Malnutrition  294 Jane Crawley, Martha Mwangome, James Berkley, and André Briend

19.1 Introduction  294 19.2 Mid Upper Arm Circumference (MUAC)  296 19.3 Comparison of MUAC with other Anthropometric Indices  296 19.4 MUAC: A Brief Historical Perspective  296 19.5 Technique for Measuring MUAC  297 19.6 MUAC, Mortality Risk, and Definitions of Severe Acute Malnutrition  298 19.6.1 Young Children (6–60 Months)  299 19.6.2 Infants (Below Six Months)  300 19.6.3 Older Children and Adolescents (5–19 Years)  301 19.6.4 Adults (20–60 Years)  301 19.7 Conclusions: Use of MUAC in Different Settings  301 References  302 Webliography  304 20

Spirometry for Chronic Obstructive Pulmonary Disease Due to Inhalation of Smoke from Indoor Fires Used for Cooking and Heating  306 Janet G. Shaw, Annalicia Vaughan, Emma Smith, Cai Fong, Svetlana Stevanovic, and Ian A. Yang

20.1 Introduction  306 20.2 Indoor Air Pollution from Burning Biomass  307 20.2.1 Burning of Biomass Fuels  307 20.2.2 Indoor Air Pollution and Biomass Burning  307 20.3 Mechanisms of Lung Damage from Exposure to Biomass Smoke  309 20.3.1 Cellular and Molecular Mechanisms Linking to Biomass Smoke and the Pathogenesis of COPD  309 20.3.2 Epidemiological Link Between Biomass Smoke Exposure and Airflow Obstruction  310 20.4 Biomass Smoke‐Related Chronic Obstructive Pulmonary Disease (COPD)  311 20.4.1 Patterns of Biomass Smoke‐Related COPD  311

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20.4.2 20.4.3 20.4.4 20.5

Clinical Presentation of COPD  311 Complications of Biomass Smoke Exposure  313 Treatment of Biomass‐Related COPD  314 Detecting Airflow Obstruction in Biomass Smoke‐Related COPD  314 20.5.1 Spirometry and Other Measurement Devices to Detect Airflow Obstruction  314 20.5.2 Facilities and Methods for Spirometry Testing  316 20.5.3 Training of Health Professionals to Undertake Spirometry  316 20.5.4 Other Early Detection Methods for COPD  317 20.6 Lessons Learnt from Clinical Guidelines for the Detection of Cigarette Smoking‐Related COPD  317 20.6.1 Clinical Guidelines for the Diagnosis of COPD  317 20.6.2 Early Detection Programs for COPD in LMICs: Checklists for Risk Factors and Symptoms  318 20.6.3 Implementing Programs for the Early Detection of Biomass‐Related COPD  319 20.7 Conclusions  319 ­Acknowledgments  320 Bibliography  320 Webliography  326 21

Point‐of‐Care Pulse Oximetry for Children in Low‐Resource Settings  327 Carina King, Hamish Graham, and Eric D. McCollum

21.1 Introduction  327 21.2 Hypoxemia  328 21.3 Pulse Oximetry  330 21.4 Current Situation in Low‐Resource Settings  332 21.5 Current Challenges and Future Opportunities  333 21.5.1 The Device  333 21.5.2 Users  335 21.5.3 Implementers/Facilities  336 21.5.4 Policy/Health Systems  337 21.6 Conclusions  339 ­Acknowledgments  339 Bibliography  340 Webliography  343 22

The Use of Near‐Infrared Spectroscopy to Monitor Tissue Oxygenation, Metabolism and Injury in Low Resource Settings  344 Gemma Bale, and Ilias Tachtsidis

22.1 Introduction  344 22.2 Near‐Infrared Spectroscopy  346 22.2.1 Scientific Background  346 22.2.2 Equipment  349 22.3 Clinical Applications  349 22.4 Research Applications  350 22.5 The Use of NIRS in Low Resource Settings  350

Contents

22.5.1 Malaria  351 22.5.2 Meningitis  351 22.5.3 Dengue Fever  352 22.5.4 Bladder Disease  352 22.5.5 Hydrocephalus  353 22.5.6 Neurodevelopment  353 22.6 Conclusions  355 Bibliography  356 Webliography  357 Part IV  23

Cheap imaging technologies  361

The Use of Point‐of‐Care Ultrasound in the Resource‐Limited Setting  363 Tom Heller, Michaëla A.M. Huson, Sabine Bélard, Dan Kaminstein, and Elizabeth Joekes

23.1 Introduction to Point‐of‐Care Ultrasound (POCUS)  365 23.2 Physics and Technical Aspects of Ultrasound  366 23.2.1 Physics  366 23.2.2 Ultrasound Image Orientation  367 23.2.3 Technical Aspects  368 23.2.3.1 Freeze 369 23.2.3.2 Gain 369 23.2.3.3 Depth 369 23.2.3.4 Focus 369 23.2.3.5 Measurements 369 23.3 Most Relevant POCUS Applications in the Resource‐Limited Setting  369 23.3.1 Patients after Trauma with Suspected Internal Bleeding: The FAST Scan  369 23.3.1.1 The Clinical Problem  369 23.3.1.2 Cardiac View  370 23.3.1.3 Right Flank View  371 23.3.1.4 Left Flank View  371 23.3.1.5 Pelvic View  371 23.3.1.6 Pathological Findings Pericardial Fluid  372 23.3.1.7 Pleural Fluid  372 23.3.1.8 Abdominal Fluid  373 23.3.1.9 Diagnostic and Therapeutic Decisions  373 23.3.1.10 Pearls and Pitfalls  375 23.3.2 Patients with Weight Loss or Night Sweats: The FASH Scan  375 23.3.2.1 The Clinical Question  375 23.3.2.2 Technique and Typical Ultrasound Findings  376 23.3.2.3 Abdominal Lymph Nodes  376 23.3.2.4 Spleen 376 23.3.2.5 Pathological Findings  376 23.3.2.6 Enlarged Lymph Nodes  377 23.3.2.7 Splenic Lesions  377

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23.3.2.8 23.3.2.9 23.3.3

Diagnostic and Therapeutic Implications  377 Pearls and Pitfalls  378 Patients with an Enlarged Cardiac Shadow on Chest X‐Ray and Signs of Heart Failure: The Cardiac Scan  378 23.3.3.1 The Clinical Question  378 23.3.3.2 Pathological Findings  381 23.3.3.3 Diagnostic and Therapeutic Implications  383 23.3.3.4 Pearls and Pitfalls  384 23.3.4 Patients with Acute Shortness of Breath: The Chest Scan  384 23.3.4.1 The Clinical Question  384 23.3.4.2 Technique and Typical Ultrasound Findings Technique  385 23.3.4.3 Pathological Findings  385 23.3.4.4 Diagnostic and Therapeutic Implications  387 23.3.4.5 Pearls and Pitfalls  388 23.3.5 Patients with Unilateral Leg Swelling: The Compression Deep Vein Thrombosis Scan  388 23.3.5.1 The Clinical Question  388 23.3.5.2 Technique and Typical Ultrasound Findings  388 23.3.5.3 Diagnostic and Therapeutic Implications  388 23.3.5.4 Pearls and Pitfalls  389 23.3.6 Patients with Hypotension of Unknown Cause: The RUSH Scan  390 23.3.6.1 The Clinical Question  390 23.3.6.2 Cardiac Status (“Pump”)  390 23.3.6.3 Intravascular Volume Status (“Tank”)  390 23.3.6.4 Examination of the Vessels (“Pipes”)  390 23.3.6.5 Pathological Findings  391 23.3.6.6 Intravascular Volume Status (“Tank”)  391 23.3.6.7 Examination of the Vessels (“Pipes”)  392 23.3.6.8 Diagnostic and Therapeutic Implications  392 23.3.6.9 Pearls and Pitfalls  393 23.3.7 Patient with Flank Pain: The Renal Scan  393 23.3.7.1 The Clinical Question  393 23.3.7.2 Technique and Typical Ultrasound Findings  394 23.3.7.3 The Bladder  394 23.3.7.4 Pathological Findings  394 23.3.7.5 Stone Disease/Calcifications  395 23.3.7.6 Bladder 395 23.3.7.7 Schistosomiasis 395 23.3.7.8 Diagnostic and Therapeutic Implications  395 23.3.7.9 Pearls and Pitfalls  396 23.3.8 Female Patient of Childbearing Age with Pelvic Pain or Vaginal Bleeding: The Ectopic Pregnancy (EP) Scan  396 23.3.8.1 The Clinical Question  396 23.3.8.2 Technique and Typical Ultrasound Findings Technique  397 23.3.8.3 Pathological Findings  397 23.3.8.4 Diagnostic and Therapeutic Implications  398 23.3.8.5 Pearls and Pitfalls  398 23.3.9 Patient with Soft Tissue Pain or Swelling: The Soft Tissue Scan  398

Contents

23.3.9.1 The Clinical Question  398 23.3.9.2 Technique and Typical Ultrasound Findings Technique  399 23.3.9.3 Pathological Findings  399 23.3.9.4 Diagnostic and Therapeutic Implications  401 23.3.9.5 Pearl and Pitfall  402 23.4 Considerations for Teaching and Implementation  402 23.5 Conclusions  403 Bibliography  403 Webliography  405 24

The Use of Obstetric Ultrasound in Low Resource Settings  406 Helen Allott

24.1 Introduction  406 24.2 Pregnancy‐Related Problems for Which Portable Ultrasound may be Useful  406 24.3 Problems with the Use of Ultrasound Scanning in Limited Resource Settings  407 24.4 Provision of Trained Sonographers  409 24.5 The Perspective of the Pregnant Woman to Antenatal Ultrasound Scanning  410 24.6 Abuse of Ultrasound Scanning in Pregnancy  410 24.7 Advances in Ultrasound Technology (and See Chapter 23)  411 24.8 Targeted Ultrasound Scanning  412 24.9 Conclusions  412 ­References  413 25

Examining the Optic Fundus and Assessing Visual Acuity and Visual Fields Using Mobile Technology  414 Nigel M. Bolster, and Andrew Bastawrous

25.1 Introduction: The Ascent of Mobile Technology  414 25.2 Visual Acuity  418 25.3 Visual Fields  424 25.4 Smartphone Ophthalmoscopy  427 25.5 Discussion  432 25.6 Conclusions  434 25.6.1 Competing Interests  434 Bibliography  434 Webliography  437 Part V Telemedicine  26

439

Telemedicine for Clinical Management of Adults in Remote and Rural Areas  441 Farhad Fatehi, Monica Taylor, Liam J. Caffery, and Anthony C. Smith

26.1 Introduction  442 26.2 Definitions  443 26.3 Types of Service  444

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26.4 26.5 26.6

Purposes of Telemedicine  444 Telemedicine for Improving Access to Care  445 Establishing a Sustainable Telehealth Network: A Case Study from Brazil  445 26.7 Swinfen Telemedicine: A Case Study of Intercontinental Telemedicine  446 26.8 Telemedicine in Natural Disaster Responses  446 26.8.1 Role of Telemedicine in Earthquake Relief Operations: A Case Study of the Nepal Earthquake in 2015  447 26.9 Telemedicine for Remote Training of Healthcare Professionals  447 26.9.1 ECHO (Extension for Community Healthcare Outcomes): A Case Study of an Online Community of Practice  448 26.9.2 The RAFT Network: A Case Study of Humanitarian Telemedicine in Africa  449 26.10 Telemedicine for Mental Health (and see Chapter 29)  449 26.10.1 Telemedicine for Suicide Prevention: A Case Study from Sri Lanka  450 26.10.2 Telemedicine for Mental Health in a Conflict Setting: A Case Study from Syria  450 26.11 The Rise of Mobile Health (mHealth)  451 26.11.1 A Low Cost Mobile‐Based Eye Care System: A Case Study of Kenya (and see Chapter 25)  452 26.12 Social Networking for Clinical Purposes  452 26.12.1 Using Telegram Instant Messaging for Clinical Consultation: A Case Study from Iran  453 26.12.2 Short Message Service (SMS) in Healthcare  453 26.12.3 Short Message Service for Improving Maternal and Child Health: A Case Study from Rwanda  454 26.13 The World Health Organization and Telemedicine  456 26.14 Challenges and Barriers to Implementation  457 26.14.1 Funding  457 26.14.2 Lack of Evidence of Effectiveness  457 26.14.3 Reimbursement  458 26.14.4 Sustainability  458 26.14.5 Legal Issues  458 26.14.6 The Future of Telemedicine  458 26.15 Conclusions  459 Bibliography  460 Webliography  461 27

Telemedicine for the Delivery of Specialist Pediatric Services  462 Anthony C. Smith, Monica Taylor, Farhad Fatehi, and Liam J. Caffery

27.1 Introduction  463 27.2 Technical Consideration for Telemedicine in LMICs  464 27.2.1 Real‐Time  464 27.2.2 Store‐and‐Forward  464 27.2.3 Internet Connectivity  465 27.2.4 Mobile Devices  465 27.2.5 Telemedicine Platforms for Low‐Resource Settings  466

Contents

27.2.6 Videoconferencing  466 27.2.7 Apps for Smart Devices  466 27.2.8 Email  467 27.2.9 Hosted Services  467 27.2.10 Smartphone‐Attached Devices  467 27.3 Models of Care in Telepediatrics  469 27.4 Swinfen Charitable Trust Telemedicine Service  469 27.5 Selected Examples of SCT Referrals  470 27.5.1 Neurosurgery  470 27.5.2 Dermatology  471 27.5.3 Orthopedics  473 27.6 National and International Telemedicine Services  474 27.6.1 Telemedicine Services in Tanzania  474 27.6.2 Médecins Sans Frontières  474 27.6.3 Case Conferencing in LMICs  475 27.6.4 Medical Missions for Children  475 27.7 mHealth Applications for LMICs  475 27.8 Telemedicine Screening Services  476 27.9 Telemedicine Support during Disaster Situations  476 27.10 Challenges Associated with Telemedicine Adoption in LMICs  477 27.11 Telepediatric Case Studies in LMICs  478 27.11.1 Pediatric Cardiology  478 27.11.2 Cancer Care Services  478 27.11.3 Orthopedics  479 27.11.4 Pediatric Surgery  479 27.12 Pathology Services  480 27.13 Radiographic (Imaging) Services  480 27.14 Maternal Health Services  481 27.15 Conclusions  481 27.16 Acknowledgements  481 27.17 Useful Websites  481 Bibliography  482 Webliography  486 28

Telemedicine in the Diagnosis and Management of Skin Diseases  488 Giselle Prado, Odinaka Anyanwu, and Carrie Kovarik

28.1 Introduction  489 28.2 Methods of Delivering Teledermatology: Store and Forward Versus Live Interactive Methods  490 28.3 The History of Teledermatology  490 28.4 Global Teledermatology Programs  490 28.4.1 Swinfen Charitable Trust  490 28.4.2 Médecins Sans Frontières  491 28.5 Teledermatology in Africa  491 28.5.1 The Africa Teledermatology Project  491 28.5.2 The Réseau en Afrique Francophone pour la Télémédecine (RAFT) network (The Network in Francophone Africa for Telemedicine)  492

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28.5.3 The Institute of Tropical Medicine (ITM) Telemedicine Website  492 28.5.4 Mobile Teledermatology in Africa  493 28.6 BUP: The Botswana – University of Pennsylvania Partnership  493 28.7 Teledermatopathology in Botswana  494 28.8 Diagnostic Concordance  495 ­28.9 Teledermatology in Asia  497 28.10 Teledermatology in Latin America  497 28.10.1 Teledermatology in Mexico  497 28.10.2 Teledermatology in Belize  498 28.11 Barriers  498 28.12 Costs  499 28.13 Education and Training  499 28.14 Equipment and Internet Access  499 28.15 Privacy Concerns  500 28.16 Cultural Hesitancy  500 28.17 Language Barriers  501 28.18 Availability of Treatments  501 28.19 Legal Issues  501 28.20 Follow‐up  501 28.21 Ensuring Success of a New Teledermatology Initiative  501 28.22 Conclusions  502 ­Bibliography  502 29

Digital Technology, Including Telemedicine, in the Management of Mental Illness  505 John A Naslund, Sophia M. Bartels, and Lisa A. Marsch

29.1 Introduction and Background  505 29.2 Why Mental Disorders?  506 29.3 Growing Access to Digital Technology and New Opportunities  508 29.4 Promising Examples from Low‐ and Middle‐Income Countries  509 29.4.1 Prevention and Promotion  509 29.4.2 Detection and Assessment  512 29.4.3 Treatment and Management  513 29.4.4 Training and Supervision  515 29.5 Critical Assessment of the Risks and Limitations  517 29.6 Future Directions and Implications  519 29.7 Conclusions  524 Bibliography  525 Webliography  530 30

The Use of Mobile Chest X‐Rays for Tuberculosis Telemedicine  531 Meghan L. Jardon, Kelsey L. Pomykala, Ishita Desai, and Kara‐Lee Pool

30.1 Background  531 30.2 Lack of Access to Radiology  532 30.3 Implementation  532 30.4 Cost  536 30.5 Sustainability  536

Contents

30.6 Chest X‐Ray Information Technology (IT)  538 30.6.1 Imaging Device Systems  538 30.6.2 Transfer of Images  539 30.6.3 Image Interpretation and Quality Assurance IT  540 30.7 Mobile Devices  540 30.8 Education to Ensure Sustainability  541 30.9 Conclusions  542 Bibliography  542 Webliography  545 Part VI  31

The future  549

An Introduction to Digital Health  551 Kerry Atkinson

31.1 Introduction  552 31.2 The Pillars and Components of Digital Health for Use in the LMICs  552 31.3 Smartphones and Internet Access  554 31.4 Wearables  555 31.4.1 The Apple Watch Series 3 and 4  556 31.4.2 AliveCor’s ECG Reader  556 31.4.3 The MOCAheart Device  557 31.4.4 Digital Contact Lens for Measuring Glucose Levels  557 31.5 Personal Digital Assistants and Chatbots  558 31.6 Augmented Reality  558 31.7 Big Data  558 31.8 Artificial Intelligence (AI)  558 31.8.1 The Application of AI to Data Management  559 31.8.2 The Increasing Complexity of Algorithms  559 31.8.3 The Advent of Intelligent Machines  559 31.8.4 The Increasing Use of AI  560 31.8.5 Current Uses of AI  561 31.8.5.1 Athletes 561 31.8.5.2 Radiology 561 31.8.5.3 Oncology 561 31.8.5.4 Dermatology 562 31.8.5.5 Cardiology 562 31.8.5.6 Gastroenterology 562 31.8.5.7 Surgery 563 31.8.5.8 Genetics and Genomics  563 31.8.5.9 Medications 563 31.9 The Game Changer – A Smartphone with AI Access  563 31.10 Conclusions  564 Bibliography  564 Webliography  564

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32

Digital Health in Low- and Middle-Income Countries  566 Martin Seneviratne and David Peiris

32.1 Introduction – The Digital Health Revolution  567 32.2 The Current Landscape  569 32.3 HIV/AIDS  569 32.4 Diabetes Mellitus  570 32.5 Maternal Health  570 32.6 Core Functionalities  571 32.7 Patient‐facing Functions  571 32.7.1 Patient Education  571 32.7.2 Service Linkage and Reminders  572 32.7.3 Self‐management and Remote Monitoring  572 32.7.4 Medication Adherence  573 32.7.5 Financing and Insurance  573 32.8 Clinician‐facing Functions  573 32.8.1 Clinical Decision Support  573 32.8.2 Specialist Advice  574 32.8.3 Communication and Workflow  574 32.9 Electronic Medical Record Management  574 32.10 Point‐of‐Care Diagnostic Tests  575 32.11 Epidemiology  575 32.12 Inventory Management and Supply Chain  575 32.13 Challenges to Scale  575 32.13.1 Evidence‐based Practice  576 32.13.2 Integration into Clinical Workflows  576 32.13.3 Financial Sustainability  576 32.13.4 Technical Scalability  577 32.14 Emerging Trends and Future Vision  578 32.14.1 Modularity and Application Programming Interfaces (APIs)  578 32.14.2 Personal Health Clouds  578 32.14.3 Social Care Models  579 32.14.4 Home‐based Care  579 32.14.5 Crowdsourced Medical Advice  579 32.14.6 Artificial Intelligence (AI)  579 32.14.7 Blockchain Technologies  579 32.15 Conclusions  580 Bibliography  580 Webliography  583 33

Nucleic Acid Detection of Tuberculosis Via Innovative Point‐of‐Care Nanotechnologies Targeted for Low Resource Settings  584 Benjamin Y.C. Ng, Eugene J.H. Wee, Nicholas P. West, and Matt Trau

33.1 Introduction  584 33.2 Nucleic Acid Detection of Tuberculosis  585 33.3 The Availability of Rapid Diagnostic Tests at the Peripheral Healthcare Level  585 33.4 Leveraging Innovative Nanotechnologies for Point‐of‐Care TB Diagnosis  587

Contents

33.4.1 Nucleic Acid Amplification Tests (NAATs)  587 33.4.2 Loop Mediated Isothermal Amplification (LAMP)  588 33.4.3 Recombinase Polymerase Amplification  589 33.5 Sample Preparation Workflow  589 33.6 Nanotechnologies for TB DNA Sensing and Readouts  590 33.6.1 Naked Eye Detection of TB DNA  591 33.6.2 Bridging Flocculation  591 33.6.3 Colorimetric Readouts  592 33.7 Quantitative DNA Detection Methodologies  592 33.7.1 Differential Pulse Voltammetry with Gold Nanoparticles  593 33.7.2 Ampometry and Spectrophotometry with TMB  594 33.8 Drug‐resistant Tuberculosis  594 33.8.1 Specific Detection of Point Mutations in M. tuberculosis DNA  595 33.9 Conclusions  595 ­References  596 34

The Use of Functional Nanoparticles for Water Purification  600 Jing Zhang, Chuanping Feng, and Chengzhong Yu

34.1 Introduction  600 34.2 Disinfection  602 34.2.1 Disinfectants  602 34.2.2 Anti‐fouling Membranes to Improve the Performance of Water Filters  605 34.3 Adsorption  607 34.3.1 Membranous Adsorbent Filter  607 34.3.2 Other Multifunctional Adsorbents  607 34.4 Electrochemistry  609 34.5 Conclusions and Future Perspectives  609 ­References  610 35

35.1 35.2

The Use of Drones in the Delivery of Rural Healthcare  615 Debrah I. Boeras, Blanche C. Collins, and Rosanna W. Peeling

Challenges in Healthcare Delivery – Opportunities for Innovation  616 The Need for Disruptive Solutions for Healthcare Delivery in Rural Areas  616 35.3 The Use of Drones for Healthcare Delivery  617 35.3.1 Modes of Operation for Drones  617 35.3.2 Delivery in Disasters and Health Emergencies  618 35.3.3 Transporting Blood and Specimens  619 35.3.4 Transporting Medicines and Medical Supplies  620 35.3.5 Vaccine Delivery  620 35.3.6 Anti‐venom Delivery  621 35.3.7 Diagnostic Test Kit Delivery  621 35.4 Further Focus on Uptake of Drone Technology by Different Countries  621 35.4.1 Malawi  621 35.4.2 Rwanda  622 35.4.3 Tanzania  622 35.5 Models of Potential Public‐Private Collaboration  622

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35.6 Promises and Challenges of the Use of Drones in Healthcare Delivery  623 35.7 Outlook for the Future  624 35.7.1 Manual Versus Automatic Control of Drones  624 35.7.2 Delivering Within Hospitals  624 35.8 Conclusions  626 Bibliography  626 Webliography  630 36

Implementation of Point‐of‐Care Tests: Lessons Learnt  633 Rosanna W. Peeling, and Debrah I. Boeras

36.1 Synopsis  633 36.2 Healthcare Needs in Low‐ and Middle‐Income Countries  634 36.3 Rapid Diagnostic Tests for Human Immunodeficiency Virus (HIV) Disease (and See Chapter 4)  636 36.4 Rapid Diagnostic Tests for Syphilis (and See Chapter 6)  637 36.5 Rapid Diagnostic Tests for Tuberculosis (TB) (and See Chapter 5)  638 36.6 Rapid Diagnostic Tests for Malaria (and See Chapter 7)  638 36.7 Lessons Learnt from the Implementation of POC Tests  639 36.7.1 Policy Barriers  639 36.7.2 Implementation Barriers  640 36.7.3 Architecture  640 36.8 Lessons Learnt from the Implementation of POC Tests for Three Diseases  640 36.9 The Way Forward  642 36.9.1 Delivering Interventions  642 36.9.2 Access as a Human Right  642 36.9.3 A Package of Care  643 36.10 The New Paradigm for Technological Innovation and Implementation  643 36.11 Conclusions  644 Bibliography  644 Webliography  648 37

Useful Electronic Healthcare Resources Available for Those Working in Remote Settings  649 Tyler Evans

37.1 Introduction  649 37.2 General Web‐Based Resources  650 37.3 Travel Medicine  651 37.4 The Big Three Communicable Diseases in Low‐ and Middle‐Income Countries (LMICs)  652 37.4.1 Malaria  652 37.4.2 HIV/AIDS  653 37.4.3 Tuberculosis  655 37.5 Hepatitis C  656 37.6 Other Infectious Diseases (IDs)  657 37.7 Dermatology  657 37.8 Obstetrics and Gynecology  658

Contents

37.9 Pediatrics  658 37.10 Psychiatry  658 37.11 Emergency Medicine (EM)  659 37.12 Preventive Health  659 37.13 Disease Mapping  660 37.14 Pharmaceuticals  660 37.15 Online Courses  661 37.16 Recommended Books  661 37.17 Institutions, Societies and Books  662 Webliography  663 38

38.1 38.1.1

The Future – How Do We Get from Here to There?  666 Kerry Atkinson and David Mabey

Progress to Date  667 Report on The United Nations Millenium Development Goals (MDGs)  667 38.1.2 The Bill and Melinda Gates Foundation Letter, 2017  667 38.1.3 Other Issues  668 38.2 Major Factors Adversely Affecting Global Health  670 38.2.1 Global Population Growth  670 38.2.2 Global Warming  671 38.2.3 Famine and Food  672 38.2.4 Drought and Drinkable Water  672 38.2.4.1 Drought 672 38.2.4.2 Water‐Borne Diseases  673 38.2.4.3 Provision of Clean Drinkable Water  673 38.2.5 Sanitation  673 38.2.6 War  673 38.3 Continue Doing What Works  674 38.4 New Measures for Improving Remote Rural Healthcare  674 38.4.1 The Success of Rapid Diagnostic Tests (RDTs) at the Primary Point‐of‐Care and Their Further Development  674 38.4.2 The Development of Cheap Innovative Imaging and Other Diagnostic Tests for Provision of Long Distance Medical Advice and Clinical Management  674 38.4.3 The Use of Telemedicine  675 38.4.4 Novel Approaches to Sanitation  675 38.4.5 A Paradigm Change in the Work Force at the Primary Point‐of‐Care Delivery  675 38.4.6 The Use of Digital Technology at the Primary Point‐of‐Care  676 38.4.7 The Supply and Quality of Health Professionals in Remote Rural Areas  676 38.4.8 New Ways Forward for Neglected Tropical Diseases  676 38.4.8.1 WHO’s Overall Approach  676 38.4.8.2 Control of Zoonoses  676 38.4.8.3 The WASH Program  677 38.4.8.4 Snake Bite  677 38.5 The UN 2015 Sustainable Development Goals for 2016–2030  677

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Contents

38.5.1 38.5.2

The 17 Sustainable Development Goals  677 Details of the Goals Directly or Indirectly Benefiting Health Outcomes  679 38.5.2.1 No Poverty  679 38.5.2.2 Zero Hunger  679 38.5.2.3 Good Health and Well‐Being  679 38.5.2.4 Quality Education  679 38.5.2.5 Gender Equality  680 38.5.3 Reactions to the Goals: Are The Sustainable Development Goals Feasible?  680 38.6 Conclusions  681 Bibliography  682 Webliography  683 Glossary  684 Index  693

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Editor’s Preface I­ first became interested in tropical medicine 50 years ago when I did an elective period as a medical student at Makerere University and Mulago Hospital in Kampala, Uganda. Searing medical images from that visit remain vivid to me to this day. One of the most enduring was the sight of six men in a male inpatient ward each having a tuberculous empyema drained. Another event was memorable: I was waiting to pay my respects to the Dean of the Medical School on the day I arrived when a man came down the corridor and sat down next to me. He asked what I was doing and I told him. I asked him what he was doing and he told me he was going “on a cancer safari.” I asked him, embarrassingly, if it was “anything to do with that Burkitt’s thing?” He turned and looked at me and said “I am Burkitt.” Serendipity, however, played its role and I subsequently found myself in medical oncology and through that into hematopoietic stem cell transplantation. A number of coincidences occurred. One of my pathology lecturers at the Middlesex Hospital Medical School in London was Tony Epstein, who co‐discovered the Epstein‐Barr virus that Denis Burkitt was tracking and relating its location in Africa with that of Burkitt’s lymphoma. Later when I was at the Royal Marsden Hospital in London, Peter Clifford was an ENT surgeon there. In fact he removed our youngest daughter’s tonsils while my wife Pauline and I were working there. Peter had previously worked for many years in East Africa and realized that the only therapeutic approach to most cases of Burkitt’s lymphoma was the use of high‐dose chemotherapy. To apply this, however, he knew that he had to harvest and cryopreserve the patient’s marrow cells prior to the chemotherapy in order to infuse them after the chemotherapy in order to reconstitute the patient’s hematopoietic system previously destroyed by the chemotherapy. To perform this Peter hired Reginald Clift, who had been working in pathology in England. E. Donnall Thomas, who pioneered bone marrow transplantation in Seattle and who won the Nobel Prize in Medicine in 1989 for it, heard of this work and promptly hired Reg to work with him in Seattle. After the Marsden I spent five years on Don’s unit in Seattle and got to know Reg well. I’m not sure how many degrees of separation this amounts but it is certainly less than six. Fast forward four decades: I left oncology and stem cell transplantation and went back to my original interest in tropical medicine. I enrolled in the spectacular East Africa course in Tropical Medicine and Hygiene organized each year by Dr Philip Gothard from the London School of Hygiene and Tropical Medicine and held over three months in Tanzania and Uganda. I had been working on a mesenchymal stem cell book with John Wiley Publishers over the preceding two years and during the African course I received an email from them asking if there was any other area of medicine that

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Editor’s Preface

I would be interested in writing about. At this time we were learning on the course about rapid diagnostic tests and innovative cheap medical imaging technologies so I asked them if they would be interested on a book on these new and other exciting innovative developments in tropical medicine. It was on the course that I met David who agreed to edit the book with me and without whom this manuscript would never have materialized. Sydney, 2019

Kerry Atkinson

­David Mabey After medical school and core medical training in the UK I went to work as a clinician at the Medical Research Council Unit in The Gambia, where I spent eight years. For the last four years I was in charge of the clinical services at the unit, which comprised a 40 bed medical and pediatric ward and an outpatient department which saw about 12 000 patients per year. In 1986 I moved back to the UK as a Clinical Senior Lecturer at the London School of Hygiene & Tropical Medicine (LSHTM) with an honorary Consultant Physician post at the Hospital for Tropical Diseases.  I ran the DTM&H course at LSHTM for a number of years, and later helped Phil Gothard to set up the East African DTM&H course. My research has focused on sexually transmitted infections (STIs) and neglected tropical diseases (NTDs) in Africa and Asia, in particular on diseases caused by Chlamydia trachomatis and Treponema pallidum, which cause both STIs and NTDs. London, 2019

David Mabey

­Acknowledgments We would both like to acknowledge the tremendous expertise, knowledge and willingness to contribute demonstrated by all the authors and co-authors in this book. Any book is only as good as its content and we feel very lucky to have been able to tap the content that has been shared with us. We would also like to thank the staff at Wiley for their capability in shepherding the book through each of its phases – Antony Sami, Metilda Shummy, Shalisha Sukunya, Ramprasad Jayakumar and especially Mindy Okura-Marszycki who commissioned the book three and a half years ago.

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List of Contributors Helen Allott

I.G. Barr

The Liverpool School of Tropical Medicine Liverpool UK

WHO Collaborating Centre for Reference and Research on Influenza Victorian Infectious Disease Reference Laboratory (VIDRL) Doherty Institute Melbourne, Victoria, Australia; Department of Microbiology and Immunology Faculty of Medicine, Dentistry and Health Sciences University of Melbourne Parkville Victoria Australia; Faculty of Science and Technology Federation University Churchill Victoria Australia

Odinaka Anyanwu

Ross University School of Medicine and University of Texas Southwestern Dallas TX USA Kerry Atkinson

University of Queensland Centre for Clinical Research Brisbane Queensland Australia; The University of Technology/Institute of Health and Biomedical Innovation Brisbane Queensland Australia Gemma Bale

Department of Medical Physics and Biomedical Engineering University College London UK

Sophia M. Bartels

Dartmouth College Hanover NH USA Andrew Bastawrous

Faculty of Infectious & Tropical Diseases Clinical Research Department London School of Hygiene and Tropical Medicine International Centre for Eye Health (ICEH) London UK

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List of Contributors

Sabine Bélard

Nigel M. Bolster

Department of Pediatric Pneumology and Immunology Charité‐Universitätsmedizin Berlin Germany; Berlin Institute of Health Berlin Germany

University of Strathclyde Biomedical Engineering Glasgow UK

James Berkley

Centre for Tropical Medicine and Global Health University of Oxford Oxford UK; KEMRI/Wellcome Trust Research Programme Kilifi Kenya; The Childhood Acute Illness and Nutrition Network (CHAIN) Nairobi Kenya

André Briend

University of Tampere School of Medicine and Tampere University Hospital Tampere Finland; Department of Nutrition, Exercise and Sports Faculty of Science University of Copenhagen Copenhagen Denmark Colin Brown

Institute of Tropical Medicine Antwerp Belgium; DNDi Geneva Switzerland; Geneva University Hospitals Geneva Switzerland

King’s Sierra Leone Partnership, King’s Centre for Global Health, King’s Health Partners King’s College London London UK; National Infection Service, Public Health England London UK; Department of Infection Royal Free Hampstead NHS Trust London UK

Debrah I. Boeras

Philippe Büscher

International Diagnostics Centre Clinical Research Department London School of Hygiene & Tropical Medicine London, UK; Global Health Impact Group Atlanta GA USA

Department of Biomedical Sciences Institute of Tropical Medicine Antwerp Belgium

Marleen Boelaert

Liam J. Caffery

Centre for Online Health Faculty of Medicine The University of Queensland Brisbane Queensland Australia

List of Contributors

François Chappuis

Tyler Evans

Institute of Tropical Medicine Antwerp Belgium; DNDi Geneva Switzerland; Geneva University Hospitals Geneva Switzerland

AIDS HealthCare Foundation Los Angeles CA USA

Blanche C. Collins

Centers for Disease Control and Prevention Center for Surveillance, Epidemiology and Laboratory Services Atlanta GA USA Jane Crawley

Centre for Tropical Medicine and Global Health University of Oxford Oxford UK Jane Cunningham

Global Malaria Program, World Health Organization Geneva Switzerland Ishita Desai

Department of Radiology University of California, Los Angeles Los Angeles CA USA Lauren Duckworth

Flinders University Adelaide South Australia Australia

Farhad Fatehi

Centre for Online Health Faculty of Medicine The University of Queensland Brisbane Queensland Australia Dunia Faulx

PATH (www.path.org) Chuanping Feng

School of Water Resources and Environment China University of Geosciences (Beijing) Beijing China Cai Fong

Thoracic Research Centre Faculty of Medicine The University of Queensland Brisbane Queensland Australia Hamish Graham

Centre for International Child Health University of Melbourne Murdoch Research Children’s Institute The Royal Children’s Hospital Melbourne Victoria Australia

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List of Contributors

Heiner Grosskurth

Catherine Houlihan

London School of Hygiene and Tropical Medicine Department of Infectious Disease Epidemiology, based at the Mwanza Intervention Trials Unit (MITU) National Institute for Medical Research (NIMR) Dar es Salaam Tanzania

Department of Infection and Immunity University College London London UK

Heather Halls

Flinders University Adelaide South Australia Australia Michael Harrison

Sullivan Nicolaides Pathology Brisbane Queensland Australia Epco Hasker

Department of Public Health Institute of Tropical Medicine Antwerp Belgium Tom Heller

Lighthouse Clinic Kamuzu Central Hospital Lilongwe Malawi Heidi Hopkins

Faculty of Infectious and Tropical Diseases London School of Hygiene and Tropical Medicine London UK

A.C. Hurt

WHO Collaborating Centre for Reference and Research on Influenza Victorian Infectious Disease Reference Laboratory (VIDRL) Doherty Institute Melbourne Victoria Australia; Department of Microbiology and Immunology Faculty of Medicine, Dentistry, and Health Sciences University of Melbourne Parkville Victoria Australia Michaëla A.M. Huson

Center of Tropical Medicine and Travel Medicine Division of Infectious Diseases Academic Medical Center University of Amsterdam Amsterdam The Netherlands Meghan L. Jardon

Department of Radiology University of California, Los Angeles Los Angeles CA USA

List of Contributors

Joseph N. Jarvis

Veerle Lejon

Department of Clinical Research Faculty of Infectious and Tropical Diseases London School of Hygiene and Tropical Medicine London UK; Botswana‐UPenn Partnership Gaborone Botswana; University of Botswana Gaborone Botswana; Division of Infectious Diseases Perelman School of Medicine University of Pennsylvania Philadelphia PA USA

Unité Mixte de Recherche IRD‐CIRAD 177 INTERTRYP Institut de Recherche pour le Développement Montpellier France

Elizabeth Joekes

David Mabey

Department of Radiology Royal Liverpool University Hospitals Liverpool UK

Clinical Research Department London School of Hygiene and Tropical Medicine London UK

Dan Kaminstein

Department of Emergency Medicine and Hospitalist Service Medical College of Georgia at Augusta University Augusta GA USA

Richard Lessells

KwaZulu‐Natal Research Innovation and Sequencing Platform Nelson R Mandela School of Medicine University of KwaZulu‐Natal Durban South Africa; Department of Clinical Research London School of Hygiene and Tropical Medicine London UK

Eric D. McCollum

Institute for Global Health University College London London UK

Department of Pediatrics, Eudowood Division of Pediatric Respiratory Sciences Johns Hopkins School of Medicine Baltimore MD USA; Department of International Health Johns Hopkins Bloomberg School of Public Health Baltimore MD USA

Carrie Kovarik

Michael Marks

Dermatology, Dermatopathology, and Infectious Diseases University of Pennsylvania Philadelphia PA USA

Clinical Research Department London School of Hygiene & Tropical Medicine London UK

Carina King

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List of Contributors

Lisa A. Marsch

Dartmouth College Hanover NH USA Hannah K. Mitchell

School of Chemistry and Molecular Biosciences The University of Queensland Brisbane Queensland Australia

Botswana‐UPenn Partnership Gaborone Botswana

Roger B. Peck

Lara Motta

International Diagnostics Centre Clinical Research Department London School of Hygiene & Tropical Medicine London UK

Flinders University Adelaide South Australia Australia Claire Mullender

St George’s Healthcare Trust London UK Martha Mwangome

KEMRI/Wellcome Trust Research Programme Kilifi Kenya Amina Nardo‐Marino

Department of Haematology, Herlev and Gentofte Hospital University of Copenhagen Herlev Denmark John A. Naslund

Harvard Medical School Boston USA Benjamin Y.C. Ng

Centre for Personalized NanoMedicine Australian Institute for Bioengineering and Nanotechnology The University of Queensland Brisbane Queensland Australia;

PATH (www.path.org) Rosanna W. Peeling

David Peiris

George Institute for Global Health Sydney Australia; and University of New South Wales Sydney Australia Kelsey L. Pomykala

Department of Radiology University of California, Los Angeles Los Angeles CA USA Kara‐Lee Pool

Department of Radiology University of California, Los Angeles Los Angeles CA USA Giselle Prado

Orange Park Medical Center Jacksonville FL USA

List of Contributors

Suman Rijal

Institute of Tropical Medicine Antwerp Belgium; DNDi Geneva Switzerland; Geneva University Hospitals Geneva Switzerland

Anthony C. Smith

Centre for Online Health Faculty of Medicine The University of Queensland Brisbane Queensland Australia Emma Smith

Department of Biomedical Informatics Stanford School of Medicine Stanford CA USA;

Department of Thoracic Medicine The Prince Charles Hospital Brisbane Queensland Australia; Thoracic Research Centre Faculty of Medicine The University of Queensland Brisbane Queensland Australia

and

Brooke Spaeth

Tala de los Santos

PATH (www.path.org) Martin Seneviratne

The Royal Prince Alfred Hospital Sydney NSW Australia

Flinders University Adelaide South Australia Australia

Janet G. Shaw

Svetlana Stevanovic

Department of Thoracic Medicine The Prince Charles Hospital Brisbane Queensland Australia; Thoracic Research Centre Faculty of Medicine The University of Queensland Brisbane Queensland Australia Mark Shephard

Flinders University Adelaide South Australia Australia

International Laboratory for Air Quality and Health Queensland University of Technology Brisbane Queensland Australia Ilias Tachtsidis

Department of Medical Physics and Biomedical Engineering University College London UK Monica Taylor

Centre for Online Health Faculty of Medicine The University of Queensland Brisbane Queensland Australia

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List of Contributors

Mark W. Tenforde

Division of Allergy and Infectious Diseases University of Washington School of Medicine Seattle WA USA; Department of Epidemiology University of Washington School of Public Health Seattle WA USA Matt Trau

Centre for Personalized NanoMedicine Australian Institute for Bioengineering and Nanotechnology The University of Queensland Brisbane Queensland Australia; School of Chemistry and Molecular Biosciences The University of Queensland Brisbane Queensland Australia Annalicia Vaughan

Department of Thoracic Medicine The Prince Charles Hospital Brisbane Queensland Australia; Thoracic Research Centre Faculty of Medicine The University of Queensland Brisbane Queensland Australia

Catherine J. Wedderburn

International Diagnostics Centre Clinical Research Department London School of Hygiene & Tropical Medicine London UK Eugene J.H. Wee

Centre for Personalized NanoMedicine Australian Institute for Bioengineering and Nanotechnology The University of Queensland Brisbane Queensland Australia Nicholas P. West

School of Chemistry and Molecular Biosciences The University of Queensland Brisbane Queensland Australia James Whitehorn

University College London UK Tom N. Williams

The KEMRI/Wellcome Trust Research Programme Kilifi Kenya; Imperial College London London UK Ian A. Yang

Department of Thoracic Medicine The Prince Charles Hospital Brisbane Queensland Australia;

List of Contributors

Thoracic Research Centre, Faculty of Medicine The University of Queensland Brisbane Queensland Australia Chengzhong Yu

Australian Institute for Bioengineering and Nanotechnology The University of Queensland Brisbane Queensland Australia

Jing Zhang

Australian Institute for Bioengineering and Nanotechnology The University of Queensland Brisbane Queensland Australia; School of Water Resources and Environment China University of Geosciences (Beijing) Beijing China

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1

Part I

The Health of Low‐ and Middle‐Income Countries Today

3

1 The Burden of Communicable Diseases in Low‐ and Middle‐ Income Countries Kerry Atkinson1, 2 and David Mabey 3 1

University of Queensland Centre for Clinical Research, Brisbane, Queensland, Australia The University of Technology/Institute of Health and Biomedical Innovation, Brisbane, Queensland, Australia 3 London School of Hygiene and Tropical Medicine, London, UK 2

­CHAPTER MENU 1.1 Introduction, 4 1.2 Definition of a Communicable Disease,  4 1.3 Definition of Low‐ and Middle‐Income Countries,  4 1.4 Definition of the Burden of Disease,  5 1.4.1 Disability‐Adjusted Life Years,  5 1.5 Definition of Disease Elimination,  7 1.6 Definition of Disease Eradication,  7 1.7 Definition of the Primary Point‐of‐Care,  7 1.8 The 2000 Millennium Development Goals and their Outcomes,  7 1.9 Major Individual Diseases in Low‐ and Middle‐Income Countries,  9 1.9.1 Malaria, 9 1.9.2 HIV/AIDS, 10 1.9.3 Tuberculosis, 11 1.9.3.1 Multidrug‐Resistant Tuberculosis,  15 1.9.3.2 Extensively Drug‐Resistant TB (XDR‐TB),  17 1.9.3.3 The Co‐epidemics of TB and HIV/AIDS,  17 1.10 Other Important Communicable Diseases in the LMICs,  17 1.10.1 Lower Respiratory Tract Infections,  24 1.10.1.1 WHO 24 1.10.1.2 Data Sources and Analysis  24 1.10.1.3 Global Burden of Disease Collaborators, 2016  27 1.10.2 Diarrheal Diseases,  28 1.10.3 Meningitis, 28 1.10.4 Sexually Transmitted Diseases (excluding HIV/AIDS),  28 1.10.5 Hepatitis, 28 1.10.6 Measles, 28 1.10.7 Whooping Cough,  28 1.10.8 Tetanus, 29 1.10.9 Yellow Fever,  29 1.11 ­Neglected Tropical Disease (NTDs) Prioritized by the World Health Organisation,  29 1.12 A Comparison of Health Metrics in a Developing Country (Papua New Guinea) and a Developed Country (Australia) with a 7 km Distance Between them,  31 1.13 Conclusions, 32 Bibliography, 32 Webliography, 35 Revolutionizing Tropical Medicine: Point-of-Care Tests, New Imaging Technologies and Digital Health, First Edition. Edited by Kerry Atkinson and David Mabey. © 2019 John Wiley & Sons, Inc. Published 2019 by John Wiley & Sons, Inc.

4

1  The Burden of Communicable Diseases in Low‐ and Middle‐Income Countries

1.1 ­Introduction The Global Burden of Disease 2015 Study provided a comprehensive assessment of all‐cause and cause‐specific mortality for 249 causes in 195 countries and territories from 1980 to 2015 (GBD 2015 Mortality and Causes of Death Collaborators 2016). Among its key findings were Global life expectancy from birth increased from 61·7 years in 1980 to 71·8 years in 2015. Several countries in sub‐Saharan Africa had very large gains in life expectancy from 2005 to 2015, rebounding from an era of exceedingly high loss of life due to HIV/AIDS. At the same time, many areas saw life expectancy stagnate or decline, particularly for men and in countries with rising mortality from war or interpersonal violence. Total deaths due infectious diseases declined significantly from 2005 to 2015, largely attributable to decreases in mortality due to HIV/AIDS, malaria, and acute respiratory infections in children under five years, although neonatal mortality (first month of life) has fallen very little. In 2015 rotaviral enteritis was the leading cause of under five years deaths due to diarrhea, and pneumococcal pneumonia was the leading cause of under five years deaths due to lower respiratory infections. Deaths due to acute lower respiratory illnesses have fallen overall due to the roll‐out of vaccines against measles, Streptococcus pneumoniae and Haemophilus influenzae b. Malaria, HIV/AIDS, and tuberculosis (TB) remained leading causes of death in the LMICs. This chapter describes the global burden of communicable diseases while Chapter 2 describes the global burden of non‐communicable diseases. The majority of the data in this chapter was sourced from the World Health Organization (WHO) or the Global Burden of Disease Project (GBD). Many of the references in this chapter are taken from documents, such as those produced by the WHO, which are only published online. Such documents are referenced alphabetically by the last name of the first author/s or organization in the Bibliography and by their Uniform Resource Locator (URL) in the Webliography (www  =  World Wide Web; http or https = Hypertext Transfer Protocol/s).

1.2 ­Definition of a Communicable Disease A communicable disease, also known as an infectious disease or a transmissible disease, is an illness resulting from an infection. Infectious agents include viruses, bacteria, fungi, protozoa, nematodes and prions.

1.3 ­Definition of Low‐ and Middle‐Income Countries In the past, and still currently, the phrases “developing world, developing countries and developing nations” have been used to describe countries with low individual incomes and poor health and poor education systems. However, there is a marked disparity in these parameters between different countries in the “developing world.” For this reason we have elected to use the term “low‐ and ‐middle income countries” (LMICs) in this book,

1.4  Definition of Burden of Disease

because there is an objective classification for this term (see below). In some cases, the term “resource‐limited settings” has also been used. The commonest measure for assessing a nation’s developmental status is to use the gross domestic product (GDP) per head of population (per capita) as determined by the Organisation of Economic Development (OECD). The OECD defines GDP as “an aggregate measure of production equal to the sum of the gross values added of all resident and institutional units engaged in production plus any taxes, and minus any subsidies, on products not included in the value of their outputs” (Organization for Economic Development definition of GDP 1993; http://esa.un.org/unsd/sna1993/introduction.asp). Figure 1.1 shows the GDP (PPP) per capita in US dollars for all countries in 2015. From this map it is clear that countries with a GDP per capita of US$35 000‐US$50 000 or more comprise the USA, Canada, some countries in South America, some countries in Western Europe, Saudi Arabia, the Gulf States, Brunei, Taiwan, Japan, South Korea, Australia and New Zealand. In contrast, many nations in Sub‐Saharan Africa have a GDP per capita of US$2000 or less. The World Bank classifies countries into four income groups using the gross national income (GNI) per capita (http://data.worldbank.org/indicator/NY.GNP.PCAP.CD? order=wbapi_data_value_2014+wbapi_data_value+wbapi_data_value‐last&sort= desc). The GNI per capita is the US dollar value of a country’s final income in a year, divided by its population. It reflects the average income of a country’s citizens. Knowing a country’s GNI per capita is a useful first step toward understanding the country’s economic strengths and needs, as well as the general standard of living enjoyed by the average citizen. A country’s GNI per capita tends to be closely linked with other indicators that measure the social, economic, and environmental well‐being of the country and its people. For example, generally people living in countries with higher GNI per capita tend to have longer life expectancies, higher literacy rates, better access to safe water, and lower infant mortality rates. In general, people in LMICs have a lower life expectancy, less education and less money than people in developed nations. The World Bank’s GNI per capita figures are set each year on 1 July. Economies were divided according to 2016 GNI per capita using the following ranges of income: Low income countries had a GNI per capita of US$1025 or less. Lower middle‐income countries had a GNI per capita between US$1026 and US$4035. Upper middle‐income countries had a GNI per capita between US$4036 and US$12 475. High income countries had a GNI per capita above US$12 476.

1.4 ­Definition of Burden of Disease 1.4.1  Disability‐Adjusted Life Years A commonly used metric for assessing the burden of disease is the Disability‐Adjusted Life Year (DALY) developed by the WHO, the World Bank and the Harvard School of Public Health (WHO | Metrics: Disability‐Adjusted Life Year [DALY]). The DALY is a time‐based measurement that combines years of life lost due to premature mortality and years of life lost due to time lived in health states less than ideal health. One DALY is defined as one lost year of “healthy” life, and the burden of disease

5

Figure 1.1  World map of GDP per Capita by Country. Gross domestic product (GDP) is converted to international dollars using purchasing power parity rates (PPP). World Bank, International Comparison Program database (2011–2014). GDP per capita ‐ PPP in international US $

50000 or more

35000–50000

20000–35000 10000–20000 5000–10000 2000–5000 less than 2000 no data available. Source: This image, reproduced here from Wikimedia Commons, is in the public domain because its creator, Rfassbind, has placed it there. https://commons.wikimedia.org/wiki/File:World_map_GDP_per_capita.svg. (See color plate section for the color representation of this figure.)

1.8  The 2000 Millennium Development Goals (MDGs) and Their Outcomes

is a measurement of the gap between current health status and an ideal situation where everyone lives into old age, free of disease and disability. Additional impacts are due to the cost of treatment, the cost of prevention, loss of income, loss of agricultural productivity, and loss of education (Hotez et al. 2009).

1.5 ­Definition of Disease Elimination Elimination of a disease refers to the reduction to zero (or a very low defined target rate) of new cases in a defined geographical area. Elimination requires continued measures to prevent re‐establishment of disease transmission.

1.6 ­Definition of Disease Eradication Eradication of a disease refers to the complete and permanent worldwide reduction to zero new cases of the disease through deliberate efforts. If a disease has been eradicated, no further control measures are required.

1.7 ­Definition of the Primary Point‐of‐Care The primary point‐of‐care is the first site that a sick person visits to seek treatment. This may be a traditional healer, an allied health professional such as a pharmacist, or a nurse or a doctor. It is currently rare for it to be a doctor in the LMICs. Because of low income and a long distance to medical facilities, or both, access to diagnostic and treatment clinics is difficult for many people in the LMICs. Primary point‐of‐care assessment and testing has the potential to make a significant impact on the management many diseases by accelerating diagnosis and instigating immediate treatment or by accelerating triage to an appropriate health facility.

1.8 ­The 2000 Millennium Development Goals (MDGs) and Their Outcomes In September 2000 189 heads of state adopted the United Nations (UN) Millennium Development Goals and endorsed a framework for their implementation. The plan was for countries and development partners to work together to reduce poverty and hunger and to tackle ill health, lack of education, gender inequality, lack of access to clean water and environmental degradation (United Nations Millennium Development Goals http://www.un.org/millenniumgoals/pdf/MDG_Report_2009_ENG.pdf ). The Eight Millennium Development Goals were 1) Eradication of extreme poverty and hunger 2) Achievement of universal primary education 3) Promotion of gender equality and the empowerment of women 4) Reduction in child mortality 5) Improvement of maternal health

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6) Combatting HIV/AIDS, malaria and other diseases 7) Ensuring environmental sustainability 8) Development of a global partnership for development. The MDGs were considered interdependent. They had targets of being achieved by 2015. Indicators to monitor progress were prescribed for each Goal. Summary reports from the specific health‐related MDGs are as follows and are sourced from: WHO. The Millennium Development Goals Report (2015), p. 4: http://www.un.org/ millenniumgoals/2015_MDG_Report/pdf/MDG%202015%20Summary%20web_ english.pdf. MDG Goal 4: Reduce childhood mortality rate ●●

●●

●●

●●

●●

●●

The global under‐five mortality rate has declined by more than half, dropping from 90 to 43 deaths per 1000 live births between 1990 and 2015. Despite population growth in the developing regions, the number of deaths of children under five has declined from 12.7 million in 1990 to almost 6 million in 2015 globally. Since the early 1990s, the rate of reduction of under‐five mortality has more than tripled globally. In sub‐Saharan Africa, the annual rate of reduction of under‐five mortality was over five times faster during 2005–2013 than it was during 1990–1995. Measles vaccination helped prevent nearly 15.6 million deaths between 2000 and 2013. The number of globally reported measles cases declined by 67% for the same period. About 84% of children worldwide received at least one dose of measles‐containing vaccine in 2013, up from 73% in 2000.

MDG Goal 5: Improve maternal health

Since 1990 the maternal mortality ratio has declined by 45% worldwide, and most of the reduction has occurred since 2000. ●●

●●

●●

●●

In Southern Asia the maternal mortality ratio declined by 64% between 1990 and 2013, and in sub‐Saharan Africa it fell by 49%. More than 71% of births were assisted by skilled health personnel globally in 2014, an increase from 59% in 1990. In Northern Africa the proportion of pregnant women who received four or more antenatal visits increased from 50 to 89% between 1990 and 2014. Contraceptive prevalence among women aged 15–49, married or in a union, increased from 55% in 1990 worldwide to 64% in 2015.

MDG Goal 6: Combat HIV/AIDS, malaria and other diseases ●●

●●

●●

New HIV infections fell by approximately 40% between 2000 and 2013, from an estimated 3.5 million cases to 2.1 million. By June 2014, 13.6 million people living with HIV were receiving antiretroviral therapy (ART) globally, an immense increase from just 800 000 in 2003. ART averted 7.6 million deaths from AIDS between 1995 and 2013. Over 6.2 million malaria deaths have been averted between 2000 and 2015, primarily of children under five years of age in sub‐Saharan Africa. The global malaria incidence rate has fallen by an estimated 37% and the mortality rate by 58%.

1.9  Major Individual Diseases in the LMICs: The Big Three ‐ Malaria, HIV/AIDS and Tuberculosis ●●

●●

More than 900 million insecticide‐treated mosquito nets were delivered to malaria‐ endemic countries in sub‐Saharan Africa between 2004 and 2014. Between 2000 and 2013, TB prevention, diagnosis and treatment interventions saved an estimated 37 million lives. The mortality rate fell by 45% and the prevalence rate by 41% between 1990 and 2013.

1.9 ­Major Individual Diseases in the LMICs: The Big Three ‐ Malaria, HIV/AIDS and Tuberculosis The three most important infectious diseases in the LMICs remain malaria, HIV/AIDS and tuberculosis. They are associated with poverty. It is of interest that these three diseases are the most prevalent in LMICs as geographically distant from each other as, for example, Tanzania and Papua New Guinea. 1.9.1 Malaria Almost half of the world’s population is at risk of malaria (WHO – 10 facts on malaria 2016). In 2015 90% of malaria cases and 92% of malaria deaths were in sub‐Saharan Africa. Further details on malaria are shown in Table 1.1. Table 1.1  The global annual incidence, the global prevalence, the number of global all‐age annual deaths, the number of global under five years annual deaths, the number of global all‐age DALYs lost due to malaria in 2005 and 2015 and the % change from 2005 to 2015.

Year/% change

Global annual incidence

Global prevalence

Global all‐age deaths

Global under five years deaths

2005

350–500 milliona). No figure stated by GBD Collaborators

No data from WHO. 2005 number not stated by GBD Collaborators

More than 1 milliona). 1.167 millionb)

No data from WHOa). 1.167 millionb)

2015

212 milliond). 286.8 millione)

No data from WHO. 295.7 millione)

429 000a). 730 500b)

303 000d). 474 100b)

Change from 2005 to 2015

A decrease of 15.4%e)

An increase of 29.9%e)

A decrease of 37.4%b)

A decrease of 42.8%b)

Global all‐age DALYS lost

No data from WHO.  90.4 millionc)

No data from WHO. 55.8 millionc) A decrease of 62%c)

a) WHO World Malaria Report WHO (2005). http://www.who.int/malaria/publications/ atoz/9241593199/en b) GBD 2015 Mortality and Causes of Death Collaborators (2016). c) GBD 2015 DALYs and HALE Collaborators (2016). d) World Malaria Report (2016). http://www.who.int/malaria/publications/world‐malaria‐report‐2016/ report/en e) GBD 2015 Disease and Injury Incidence and Prevalence Collaborators (2016).

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Table 1.2  The global annual incidence, the global prevalence, the number of global all‐age annual deaths, the number of global under five years annual deaths, the number of global all‐age DALYs lost due to HIV/AIDS in 2005 and 2015 and the % change from 2005 to 2015. Global under five years deaths

Global all‐age DALYs lost

3.1 milliona). 1.79 millionc)

570 000 children under 15 yearsd); No figure given in GBD Collaboratorsc)

98.9 millione)

36.7 milliona). 37.2 milliond)

1.1 milliond). 1.19 millionc)

No figure given in UNAIDS Fact sheet. 88 9004 ‐

66.7 millione)

An increase of 21%b)

A decrease of 33%c)

A decrease of 51%c)

A decrease of 39.9%e)

Year/% change

Global annual incidence

Global prevalence

Global all‐age deaths

2005

4.9 milliona). Children less than 15 years 2.3 milliona). No figure stated by GBD Collaborators

40.3 milliona).   No figure given by GBD Collaboratorsb)

2015

2.0 milliond) Children less than 15 years 150,000d)

Change from 2005 to 2015

An all‐age decrease of 41%a),d)

a) b) c) d)

WHO. AIDS epidemic update, December (2005). http://www.who.int/hiv/epi‐update2005_en.pdf?ua=1 GBD 2015 Disease and Injury Incidence and Prevalence Collaborators (2016). GBD 2015 Disease and Injury Incidence and Prevalence Collaborators (2016). UNAIDS Fact Sheet ‐ latest statistics on the status of the AIDS epidemic. http://www.unaids.org/en/ resources/fact‐sheet. e) GBD 2015 DALYs and HALE Collaborators (2016). The UNAIDS AIDS Epidemic Update (2005) lists 570 000 deaths from HIV/AIDS during 2005 but this was for children under 15 years of age rather than those under 5 years of aged).

In Tables 1.1 and 1.12 it should be noted that WHO did not routinely publish disease incidence data in 2005 or 2015. The GBD Collaborators did not always publish numbers for 2005, although they routinely calculated the % difference between 2005 and 2015. Thus, increased prevention, treatment and control measures have led to a 37.4% reduction in the malaria mortality rate globally between 2005 and 2015, a 42.8% reduction in the malaria under‐fives mortality rates globally between 2005 and 2015 and a 38% decrease in DALYs lost globally due to malaria between 2005 and 2015. The most important contributors to these improvements are the increased use of insecticide‐impregnated bed nets and access to artemisinin‐based combination therapy (ACT). Approximately half the countries with ongoing malaria transmission are on track to meet the World Health Assembly and Roll Back Malaria targets to achieve a 75% reduction in malaria cases by 2015 as compared to those in 2000. 1.9.2 HIV/AIDS More than 65 million people have been infected with HIV and 30 million people have died due to AIDS‐related causes since the emergence of AIDS in 1981. In 2015 there were 36.3 million people living with HIV including 1.8 million children less than 15 years

1.9  Major Individual Diseases in the LMICs: The Big Three ‐ Malaria, HIV/AIDS and Tuberculosis

of age. HIV/AIDS has an uneven geographical distribution with Sub‐Saharan Africa bearing more than two‐thirds of the global burden (Figures 1.2 and 1.3), followed by India and parts of Southeast Asia. The estimated number of people living with HIVin 2016 by WHO region is shown in Figure 1.2 and the number of people dying of HIV in 2016 by WHO region is shown in Figure 1.3. Further details on HIV/AIDS are shown in Table 1.2. These improvements are due to the roll out of ART treatments. As an example, ART access in 2013 averted an estimated 1 051 354 deaths in South Africa and an estimated 422 448 deaths in Nigeria (Granich et al. 2015). Additionally, 77% of pregnant women living with HIV were able to access antiretroviral medications in 2014 compared with 37% in 2009. This has halved the mother‐to‐child transmission rate of HIV across the Global Plan priority countries from 28 to 14%. These countries are Angola, Botswana, Burundi, Cameroon, Chad, Côte d’Ivoire, the Democratic Republic of the Congo, Ethiopia, Ghana, India, Kenya, Lesotho, Malawi, Mozambique, Namibia, Nigeria, South Africa, Swaziland, Uganda, the United Republic of Tanzania, Zambia, and Zimbabwe. Together, these countries accounted for 90% of the total number of pregnant women living with HIV that needed services to prevent mother‐to‐child transmission of HIV in 2009 (UNAIDS 2015 Progress Report 2015). The life expectancy of people living with HIV has dramatically increased since effective ART has been available and still continues to improve (Nakagawa et al. 2013). 1.9.3  Tuberculosis (TB) The world is continuing to experience a high burden of disease due to TB. One third of  the world’s population is infected with Mycobacterium tuberculosis. Tuberculosis is  the second most lethal communicable disease worldwide after HIV/AIDS with 1.19 million and 1.1 million deaths respectively in 2015. In 2015 there were an estimated 10.4 million new TB cases worldwide, of which 5.9 million (56%) were in men, 3.5 million (34%) in women and 1.0 million (10%) in children (WHO Global Tuberculosis Report 2016). People living with HIV accounted for 1.2 million (11%) of all new TB cases. The estimated incidence of TB in 2015 is shown in Figure 1.4. In the United States the annual incidence was  Physicians > per 1000 people: countries compared. http://www.nationmaster. com/country‐info/stats/Health/Physicians/Per‐1,000‐people.

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1  The Burden of Communicable Diseases in Low‐ and Middle‐Income Countries

Table  1.15 illustrates the huge gap in health-related metrics between these two countries.

1.13 ­Conclusions Much progress has been made the first 15 years of the twenty‐first century in malaria, HIV/AIDS, TB, neglected tropical diseases and other communicable diseases. This has been due to many factors including new vaccination programs, new medications particularly the HAART drugs for HIV/AIDS, improved sanitation, access to clean drinking water and increased public health education. Much remains to be done. New rapid diagnostic tests, the use of telemedicine, and the role of the (ubiquitous) mobile phone represent platforms for achieving further improvement. The WHO Millennium Development Goals have been replaced by the WHO Sustainable Development Goals for the period 2016 to 2030. These are much more complex and have a much wider remit than health goals alone. Some, if achieved, such as the end of global poverty, will produce a striking improvement in health in the LMICs and are addressed in Chapter 38.

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http://www.who.int/immunization/monitoring_surveillance/burden/vpd/surveillance_ type/active/measles/en ‐ WHO Measles. http://www.who.int/immunization/monitoring_surveillance/burden/vpd/surveillance_ type/active/measles/en ‐ Measles. http://www.who.int/immunization/monitoring_surveillance/burden/vpd/surveillance_ type/passive/tetanus/en WHO ‐ Tetanus. Immunization, vaccines and biologicals. http://www.who.int/malaria/publications/world‐malaria‐report‐2016/report/en ‐ WHO World Malaria Report 2016. http://www.who.int/mediacentre/factsheets/fs100/en ‐ WHO Fact sheet on yellow fever updated in May 2016. http://www.who.int/mediacentre/factsheets/fs164/en ‐ WHO Fact sheet on hepatitis C updated in April 2017. http://www.who.int/mediacentre/factsheets/fs286/en http://www.who.int/mediacentre/factsheets/fs286/en ‐ WHO Measles Fact sheet reviewed in March 2017. http://www.who.int/mediacentre/factsheets/fs310/en ‐ WHO Top 10 causes of death in 2015. Fact sheet updated in January 2017. http://www.who.int/mediacentre/factsheets/fs330/en ‐ WHO Fact sheet on diarrhoeal disease updated in May 2017. http://www.who.int/topics/millennium_development_goals/MDG‐NHPS_brochure_2010. pdf?ua=1 ‐ WHO: Accelerating progress towards the health‐related Millennium Development Goals. http://www.who.int/topics/millennium_development_goals/post2015/en ‐ WHO MDGs: Progress made in health. https://www.cdc.gov/mmwr/preview/mmwrhtml/mm5847a2.htm ‐ CDC MMWR December 2009. Global measles mortality 2000–2008. https://www.cdc.gov/pertussis/countries/index.html ‐ CDC report on pertussis in countries other than the USA. https://www.imf.org/external/pubs/ft/weo/2016/01/weodata/index.aspx ‐ World Economic Outlook Data Base, 2016. http://www.who.int/en/news‐room/fact‐sheets/detail/measles ‐ WHO Measles Fact sheet reviewed in March 2017. http://www.who.int/tb/publications/global_report/en ‐ WHO Global Tuberculosis Report, 2016. www.adi.org.au/wp‐content/uploads/2016/…/ADI‐Annual‐Report‐2015‐6_WEB.pdf ‐ Australian Doctors International Annual Report, 2015–2016.

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2 The Burden of Non‐communicable Diseases in Low‐ and Middle‐Income Countries Heiner Grosskurth London School of Hygiene and Tropical Medicine, Department of Infectious Disease Epidemiology, based at the Mwanza Intervention Trials Unit (MITU), National Institute for Medical Research (NIMR), Dar es Salaam, Tanzania

­CHAPTER MENU 2.1 2.2 2.3 2.3.1 2.3.2 2.3.3 2.3.4 2.3.5 2.3.6 2.3.7 2.4 2.5 2.6 2.7 2.7.1 2.7.2 2.7.3 2.8 2.8.1 2.8.2 2.8.3 2.9 2.10 2.10.1 2.10.2 2.10.3 2.10.4 2.10.5 2.10.6 2.10.7 2.10.8 2.10.9 2.10.10

Introduction, 38 Common Non‐communicable Diseases in Low- and Middle-Income Countries,  38 NCD Epidemiology,  38 Arterial Hypertension and Cardiovascular Diseases,  39 Diabetes Mellitus,  40 The Metabolic Syndrome,  41 Chronic Kidney Disease,  41 Chronic Obstructive Pulmonary Disease (COPD),  41 Asthma, 42 Cancer, 43 Prevention of Non‐communicable Diseases,  44 The Relationship Between Communicable and Non‐communicable Diseases,  44 The Health System Burden of NCDs,  46 The Economic Impact of NCDs,  47 The Patent’s Perspective,  47 The Provider’s Perspective,  47 Macroeconomic Effects,  48 The Response to the NCD Epidemic in LMICs,  48 Response at the International Level,  48 Response at National Level,  49 Response by the Private Sector,  50 The Readiness of Primary Healthcare Services in LMICs to Cope with the NCD Burden,  50 Introducing Effective NCD Control at Primary Care Services: A Practical Approach,  52 Raising NCD Awareness Within the Health Services,  52 Training Healthcare Workers,  52 Conducting Support Supervision,  53 Providing Essential Diagnostic Equipment and Tests,  64 Ensuring a Reliable Supply of Essential NCD Drugs,  64 Introducing Standardized NCD Case Management Algorithms,  65 Treating Patients Close to their Residence: Effective Referral and Back‐Referral,  65 Introducing Health Education and NCD Case Detection,  66 Establishing an Effective Recording System,  67 Integrating NCD Control Measures into Outreach Activities,  67

Revolutionizing Tropical Medicine: Point-of-Care Tests, New Imaging Technologies and Digital Health, First Edition. Edited by Kerry Atkinson and David Mabey. © 2019 John Wiley & Sons, Inc. Published 2019 by John Wiley & Sons, Inc.

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2.11 2.12 2.13

The Role of Primary Healthcare Services in Cancer Prevention and Care,  67 Evaluating Programs to Strengthen NCD Services at Primary Care Level,  70 Conclusions, 70 Bibliography, 70 Webliography, 78

2.1 ­Introduction This Chapter begins with a summary of the most common non‐communicable diseases (NCDs) in low‐ and middle‐income countries (LMICs). It then looks at the epidemiol­ ogy of a selection of common NCDs in LMICs and of risk factors associated with NCDs, as well as the overlap between NCDs and communicable diseases. This is followed by data on the burden that NCDs represent for health services, and the economic conse­ quences associated with NCDs at patient, health system and macroeconomic levels. Next it examines the response to the growing NCD epidemic at international and national levels, and within the private sector. The Chapter then explores how health services in LMICs currently cope with the growing NCD burden, identifying the chal­ lenges they encounter. The subsequent section provides practical guidance on how to improve the performance of NCD services, based on the experience from a control program implemented in East Africa and ends with guidance on how to evaluate pro­ grams that aim to improve NCD services at the primary healthcare level. Policy advis­ ers, health program managers and NCD control project staff may wish to find practically relevant additional information. They can find links to such material in the list of refer­ ences which whenever possible refers to open access publications.

2.2 ­Common Non‐communicable Diseases in Low- and Middle-Income Countries Non‐communicable diseases include a large and varied group of health conditions, all of which are not or not directly caused by an infectious pathogen. In public health (and in this chapter), the term “NCDs” has a much more restricted meaning and refers to a group of common chronic diseases that mainly comprise four types: cardiovascular dis­ eases including their consequences (such as ischemic heart disease and stroke), diabetes mellitus, chronic respiratory diseases (in particular chronic obstructive pulmonary dis­ ease – or “COPD,” and asthma) and cancers. These four disease groups are responsible for about 80% of NCD deaths worldwide (WHO 2014a).

2.3 ­NCD Epidemiology NCDs have been highly prevalent in industrialized countries for a long time, but in LMICs they occurred much less frequently until about the last two decades of the ­twentieth century. The burden of NCDs has since been rising in LMICs, repeating to some extent a shift of morbidity and mortality that high income countries (HICs) had experienced much earlier. In HICs this has given rise to the theory of epidemiological

2.3  NCD Epidemiology

t­ ransition (Omran 1971), and there is strong evidence that this transition has reached LMICs. For example, according to the Global Burden of Disease Study, the total number of deaths per year due to NCDs rose by approximately 14% in 2005 to approximately 40 million in 2015 (GBD 2015, 2016a), of which more than 80% have been recorded in LMICs (WHO 2014a). During the same period, the death toll attributable to communi­ cable, maternal, neonatal, and nutritional conditions significantly declined, mostly because of advances with respect to HIV disease, malaria and birth complications (GBD 2015, 2016a). Interestingly, age‐adjusted mortality rates for both NCDs and other con­ ditions have declined to some extent. However, because populations increase particu­ larly in LMICs and because overall life expectancy is increasing, the number of deaths due to NCDs is also increasing (GBD 2015, 2016a). Modeling studies predict that the proportion of deaths caused by NCDs will rise to about 70% of all deaths by about 2030 (Mathers and Loncar 2006). Globally, men and women are almost equally affected, and NCDs are not just a prob­ lem among older age groups. According to WHO estimates derived from the Global Burden of Disease study, more that 40% of all deaths due to NCDs occur below the age of 70, and this proportion is higher in LMICs than in high income countries (WHO 2014a). 2.3.1  Arterial Hypertension and Cardiovascular Diseases Hypertension is the most important risk factor for cardiovascular diseases. Hyper­ tension is characterized by an elevated usual resting blood pressure with a systolic pressure of 140 mmHg or more and/or a diastolic pressure of 90 mmHg or more (Joint  National Committee 2004). The term pre‐hypertension is used if the systolic and  diastolic blood pressure are 120–139 and/or 80–89 mmHg, respectively. These definitions are somewhat arbitrary as the mortality associated with elevated blood pressure increases for all age bands from about 115 mmHg (systolic) and from about 75 mmHg (diastolic) upwards. For example, for the age group of 40–69 years, each increase of 20 mmHg of systolic or 10 mmHg of diastolic blood pressure leads to a twofold increase in the death rate due to stroke (Lewington et al. 2002). Hypertension can be a symptom of other diseases such as a tumor or dysfunction of the adrenal glands, but in most hypertensive patients no distinct cause can be identified. Only few data have been available from LMICs for the time before the year 2000, but hypertension seems to have been an uncommon problem there until recently. For example, a survey of about 1700 men from a rural community in Kenya conducted in 1983 found no individual with hypertension, and blood pressure did not increase until approximately the age of 60 (Poulter et al. 1984). In contrast, a survey from 2012 among 2100 adults (40% men) from another rural community in Kenya, the overall prevalence of hypertension was 21%. The prevalence rose rapidly with increasing age and reached 47% in those aged 55 years and above. Additionally, 4% of young adults aged 18–24 years were affected (Hendriks et al. 2012). A high prevalence of hypertension has been reported by various other recent popula­ tion studies in African countries including Tanzania and Uganda (Kavishe et al. 2015), Namibia and Nigeria (Hendriks et al. 2012), South Africa (Rheeder et al. 2017), as well as from other LMICs outside Africa (Irazola et al. 2016). The prevalence in some groups exceeded 50%. While earlier studies showed that hypertension was more a problem of urban populations, rural areas are now equally affected.

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Several risk factors predispose to hypertension, including male gender, obesity, alco­ hol use, lack of physical exercise, increased levels of blood cholesterol, diabetes, and high salt consumption. The latter is of particular concern as a high sodium intake has become very common in LMICs (Powles et al. 2013). More than 80% of patients with hypertension found in population studies were una­ ware of their condition, and of those who are, few receive treatment and even fewer are controlled (Hendriks et al. 2012; Kavishe et al. 2015). 2.3.2  Diabetes Mellitus Diabetes mellitus type 1 is caused by an autoimmune process that results in the failure of the pancreas to produce sufficient insulin. Usually the disease begins at an early age but onset can occur at all age groups. All patients with type 1 diabetes require insulin therapy. In contrast, type 2 diabetes occurs when endogenously produced insulin is not sufficiently effective in controlling blood glucose levels. Type 2 diabetes usually begins at a higher age, but may occur in adolescents and young adults, particularly in the pres­ ence of lifestyle‐related risk factors such as obesity or lack of exercise. In general, type 2 diabetes responds well to reduction of these risk factors, but in some cases, it may require oral antidiabetic medication or even insulin. Both types of diabetes lead to com­ plications most of which result from damage to blood vessels. Complications include diabetic nephropathy, neuropathy, retinopathy and diabetic ulcers of the feet, as well as heart disease, stroke and ischemic limb disease. Diabetes thus contributes significantly to the pathogenesis of cardiovascular diseases (Alberti and Zimmet 1998), and diabetes is often also associated with hypertension. In LMICs where specialized laboratory ser­ vices are scarce, the diagnostic distinction between the two types of diabetes cannot always be accurately made, but in terms of absolute numbers, the burden of diabetes type 2 is far higher than that of diabetes type 1. Worldwide, according to WHO estimates, the prevalence of diabetes has almost dou­ bled between 1980 and 2014. This increase has been much more prominent in LMICs than in high‐income countries. Globally, more than 400 million adults are affected by diabetes, and about 1.5 million deaths occur annually due to it (WHO 2016a). In ­population‐based studies from various LMICs around the world, the prevalence of dia­ betes is usually between 5 and 10%, but ranges from 1 to 30% (Kavishe et  al. 2015; Kengne et al. 2013; Nanditha et al. 2016), and has been reported to exceed nearly 40% in some Pacific island populations (Nanditha et al. 2016). Diabetes is generally more prev­ alent in urban populations, but some studies report a high prevalence from rural areas as well (Hwang et al. 2012). Men and women are generally equally affected. The main risk factors for diabetes type 2 are overweight and obesity in combination with a lack of physical activity (GBD 2013, 2015). Other factors include a high con­ sumption of saturated fatty acids (Ley et  al. 2014), low birth weight (Whincup et  al. 2008) and smoking (Willi et al. 2007). Of particular importance for the epidemiology of diabetes in LMIC is the observation that poor fetal growth and low birth weight seem to increase the risk of developing metabolic diseases later in life (Whincup et al. 2008). Genetic factors also play a role: diabetes occurs more frequently in individuals with a family history of the disease (Dagenais et al. 2016), and people from South East Asia have a higher risk of developing diabetes than other populations, even in the absence of obesity (Ramachandran et al. 2010).

2.3  NCD Epidemiology

Diabetes type 2 often develops slowly so that patients remain unaware of their condi­ tion for a long time and therefore are not treated, thus losing valuable time for the pre­ vention of complications (Beagley et al. 2014). 2.3.3  The Metabolic Syndrome Certain risk factors for cardiovascular diseases and diabetes often appear in combina­ tion, and this occurs more often than expected by chance. These factors include ele­ vated fasting blood glucose, high triglycerides, reduced high density cholesterol, elevated blood pressure and being overweight. This combination of factors is called the metabolic syndrome. Different definitions of the metabolic syndrome can be found in the literature. More recently it has been agreed that for patients to qualify for the diag­ nosis of the syndrome, they should have at least three of these five factors, and because a higher than normal waist circumference as a marker for central obesity is frequently present, it can be used as a screening tool to detect the metabolic syndrome (Alberti et al. 2009). The presence of the metabolic syndrome is a strong predictor for develop­ ing diabetes and cardiovascular diseases. The prevalence of the metabolic syndrome in LMIC varies across countries, seems to have increased over recent years and reaches very high levels in some populations, for example, nearly 50% in some groups from Pakistan (Ranasinghe et  al. 2017). From a public health perspective, it may be a useful marker to monitor the risk for cardiovascu­ lar diseases and diabetes within populations (Ofori‐Asenso et al. 2017). 2.3.4  Chronic Kidney Disease Chronic kidney disease (CKD) is highly prevalent in LMICs. It is clinically defined as a disturbed kidney structure or function lasting longer than three months. Criteria for the diagnosis of CKD include a glomerular filtration rate (GFR) of less than 60 mL/min/1.73 m2, and/or markers of kidney malfunction such as albuminuria (ISN 2013). CKD is often a chronic complication of other NCDs, mainly diabetes and hypertension, or of specific renal diseases such as glomerulonephritis. However, there are also many CKD patients in LMICs for which an underlying cause cannot be established (Lunyera et  al. 2016). Prevalence data from LMICs are scarce, ranging from 5 to 15% in general population studies (Jha et al. 2013; Stanifer et al. 2014), but exceed 20% in some populations. CKD can result in end‐stage kidney failure, cardiovascular diseases, anemia (due to inadequate renal production of erythropoietin) and bone disorders (Jha et al. 2013) (the latter being due to the inability of damaged kidneys to balance phosphorus and calcium levels in the blood). Risk factors other than diabetes and hypertension include schistosomiasis, inflammatory diseases of the kidney, environmental toxins and poverty. CKD has greater public health importance in LMICs than is currently reflected in the NCD‐related literature. 2.3.5  Chronic Obstructive Pulmonary Disease (COPD) COPD is a chronic lung disease marked by inflammatory changes of small airways and a parenchymal damage of alveolar tissue (GOLD 2017a). COPD patients suffer from progressive dyspnea, and often also from chronic cough and sputum production. The disease is characterized by a reduction in airflow that cannot be fully reversed using a

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bronchodilator, and this is an important criterion in the differential diagnosis of COPD and asthma. The diagnosis of COPD is made by a forced vital capacity test using respirometry after applying an inhaled bronchodilator: the maximal forced expiratory volume in one second (FEV1) is reduced relative to the forced vital capacity (FVC) that a person can maximally exhale. In individuals with COPD, the FEV1/FVC ratio is less than 0.7 (GOLD 2017b). In a population‐based study from 2007 conducted in 12 sites around the world with a total sample of more than 9000 men and women, the prevalence of manifest COPD was about 10% overall, 12% among men and 9% among women. The risk of having COPD increased with age by an odds ratio of about 2 per 10‐year age increment (Buist et al. 2007). Studies from sub‐Saharan Africa showed a prevalence ranging from 2 to 25% in different populations (Finney et al. 2013; Kavishe et al. 2015), with the highest levels seen in urban South Africa. It has been estimated that globally in 2010 the number of COPD cases was more than 380 million, and that about 3 million people died from COPD per year (GOLD 2017a). Due to aging and an increase in smoking in LMICs, the expected number of deaths is predicted to rise to more than 4.5 million deaths by 2030 (Lopez et al. 2006). Key risk factors for developing COPD in LMICs include the exposure to indoor air pollution caused by cooking with biomass fuel (see Chapter 20), and in some countries tobacco smoking which is one of the main causes of COPD in high income countries. Generalized air pollution due to industry and traffic are important too. Industrial work­ ers in LMICs are often also exposed to occupational dusts and chemicals that are asso­ ciated with COPD (Mannino and Buist 2007). Low birth weight and respiratory infections during childhood increase the risk for the development of COPD in adult­ hood. Genetic factors such as deficiency of alpha‐1 antitrypsin may play a role (de Serres and Blanco 2014). 2.3.6 Asthma In contrast to COPD, asthma is a chronic disease characterized by episodes of reversi­ ble constriction of the airways. Typical symptoms include wheezing, breathlessness and sometimes cough. In susceptible patients, asthma attacks can be triggered by aller­ gens such as house dust mites, pollens, but also by tobacco smoke, polluted air, respira­ tory tract infections and physical exercise and exposure to cold water (Vernon et  al. 2012; Marks et al. 2014). In many cases an allergic cause cannot be found. Asthma often begins during childhood, but most children who have asthma become free of symptoms during adolescence. On the other hand, asthma can also newly develop later in life. Asthma is less common than COPD, but WHO estimates that worldwide, more than 230 million people have asthma (Marks et al. 2014). Reliable data on the prevalence and incidence of asthma from LMICs are scarce. For a long time, it was thought that asthma was a problem of northern populations, but there is some indication that the prevalence is rising fast and that nowadays most asth­ matic patients live in LMICs (Global Asthma Report 2014). The mortality of asthma is low, causing not more than 1% of all deaths worldwide. Nevertheless, it is believed that about 340 000 asthma patients die per year (Marks et al. 2014). Proportionally, mortality rates are higher among older persons than among children. However, in older age groups asthma patients may also have COPD, making a clear allocation of mortality rates difficult. South Africa has the highest age‐standardized asthma mortality rate worldwide with about 290 deaths per million (Global Asthma Report 2014).

2.3  NCD Epidemiology

2.3.7 Cancer Data on cancer epidemiology from LMICs are less reliable than those from high‐income countries due to the lack of systematic cancer registries in many countries (Bray et al. 2015). However, it has been estimated that more than 60% of all cancers and about 70% of cancer deaths occur in LMICs (Ferlay et al. 2015). There are wide variations in the distribution pattern of specific types of cancer between and within different regions (Forman and Ferlay 2014). Across all world regions LMICs have the highest burden of stomach, liver, esophageal and cervical cancer. As in industrialized countries, prostate, breast, lung, and colorectal cancers are also frequent (Torre et al. 2016). In line with the size of its population, Asia bears the highest burden of cancers of all world regions, and about 30% of all cancers in the world occur in China and India. The most common forms of cancer among men in Asia are lung, stomach, liver, colon and esophageal cancers, each with an age‐standardized incidence of 10 or more per 100 000 per year, and all of these cancers have high mortality rates. Although lung cancer has the highest incidence and mortality rate among men in the region (35 and 32% per 100 000 respectively), it is still substantially less frequent in Asia than in Europe and North America. Rates of liver and stomach cancer in Asian men are higher than those in other world regions. In women, as in other regions, breast cancer is the most prevalent can­ cer, but lung cancer is the most frequent cause of cancer‐related deaths (Forman and Ferlay 2014). The epidemiology of cancers in sub‐Saharan Africa (SSA) differs from other world regions in some important aspects: among women, the incidence of cervical cancer is as high as that of breast cancer, and its incidence and mortality (35/100 000 and 23/100 000 respectively) are the highest among all world regions. In men prostate cancer is the most common: prostate cancer has an incidence of 28/100 000 and the mortality rate is nearly as high as the incidence, in contrast to industrialized countries where prostate cancer mortality tends to be only about a sixth to a tenth of the incidence, largely due to more advanced options for case detection and treatment. Liver cancer too has a high incidence and mortality, each exceeding 10/100 000 in both men and women. Kaposi sarcoma1 is a common complication of advanced HIV infection, and because the bur­ den of HIV infection is higher in SSA than other regions, the incidence of this tumor is particularly high there (about 7/100 000) (Forman and Ferlay 2014). Currently the rate of Kaposi sarcoma is falling due to the increasing use of antiretroviral therapy (ART) (Bohlius et al. 2014). In Latin America, including the Caribbean subregion, breast cancer and prostate can­ cer are the most frequent forms of cancer among women and men respectively, similar to the situation in Europe and North America. However, the incidence and mortality of cervical cancer (21/100 000) is much higher than in industrialized regions, albeit not as high as in SSA. Lung, colon and stomach cancers are the second, third and fourth fre­ quent forms of cancer among both women and men. Common risk factors for the most frequent cancers include some that are also associ­ ated with other major NCDs: tobacco smoking, abuse of alcohol, low fruit and vegetable intake and obesity (GBD 2015, 2016b). Some cancers are directly caused by viral infec­ 1

  Moritz Kaposi (1857–1902) was a Hungarian physician and dermatologist who described this disease in 1872.

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2  The Burden of Non‐communicable Diseases in Low‐ and Middle‐Income Countries

tions: hepatitis B (hepatocellular cancer), hepatitis C (hepatocellular cancer), human papilloma virus infection (cervical cancer), human herpes virus 8 (Kaposi’s sarcoma), and Epstein–Barr virus (Burkitt’s lymphoma (Plummer et  al. 2016), whilst for some other forms of cancer, infections play a strong contributing role, in particular HIV infec­ tion. Increasing age is associated with various forms of cancer, probably because carci­ nogenic factors have a longer time to exert their effects and to lead to cell mutations.

2.4 ­Prevention of Non‐communicable Diseases As mentioned above, individual NCDs share a number of life‐style related risk factors, notably tobacco use, being overweight or obese, harmful use of alcohol, an unhealthy diet that is high in calories, saturated fatty acids or salt but low in fiber and vitamins, and insufficient physical work or exercise (WHO 2014a). About three‐quarters of all cases of cardiovascular diseases and diabetes can be attributed to these risk factors, and thus could be prevented. Smoking and obesity are of particular concern. Smoking alone caused about 5 million deaths in 2010, and this is expected to rise to 10 million or more over the next few decades (Jha and Peto 2014), which would then account for about 10% of all deaths. Approximately 80% of these deaths are expected to occur in LMICs. The prevalence of being overweight and obesity is surprisingly high in LMICs. In a study of more than 31 000 adults from 9 LMICs, the prevalence of central obesity (i.e. obesity determined by measuring waist circumference) ranged from 19 to 79% (Patel et al. 2016). Women seem to be more affected than men (Kavishe et al. 2015). Obesity is strongly associated with diabetes and hypertension (Patel et  al. 2016). Obesity often begins in childhood. It has been estimated that worldwide in 2015 there were 42 million overweight children (UNICEF, WHO, World Bank 2015), and this is a rapidly growing problem in LMICs also (WHO 2016a). Being overweight or obese are also associated with various types of cancer, including cancers of the breast, colon and liver (Steele 2017). Consequently, there is a need for interventions to reduce these risk factors, both in high‐income countries and LMICs. It has been estimated that, if the key NCD risk fac­ tors could be eliminated, most cases of heart disease, stroke and diabetes type 2 and about 40% of cancers would be prevented (WHO 2013a). Higher taxation on tobacco products, a ban of smoking at work and public places, a ban on alcohol advertisements and laws on the reduction of salt and saturated fatty acids in processed food could make a major contribution to this goal. Many countries, including about 40 LMICs have implemented such legislation with respect to smoking (WHO 2013a), but much less progress has been made on the other factors. Obviously, the interests of large and pow­ erful industrial companies are at odds with those of public health (Buse et al. 2017).

2.5 ­The Relationship Between Communicable and Non‐ communicable Diseases For a number of reasons, the dichotomy between communicable diseases and NCDs is not as clear‐cut as much of the current literature seems to suggest. Firstly, the distinc­ tion is blurred because some NCDs, in particular cancers, have a viral infectious origin,

2.5  The Relationship Between Communicable and Non‐communicable Diseases

for example, hepatocellular cancer (viral hepatitis B and C) cervical cancer (human pap­ illoma virus), and lymphatic tissue (Epstein–Barr virus for non‐Hodgkin lymphoma and human herpes virus 8 for Kaposi’s sarcoma). Bacterial infections can also play a role  in the etiology of cancers. For example, the risk of developing gastric cancer is doubled among individuals infected with Helicobacter pylori (Eslick 2006). Secondly, some infectious diseases are associated with NCDs. For example, HIV‐ infected patients, particularly those on anti‐retroviral therapy, seem to have a sub­ stantially higher risk of acquiring cardiovascular diseases and diabetes mellitus than HIV‐negative individuals (Dillon et al. 2013; Mathabire Rücker et al. 2017). Vice versa, some NCDs increase the risk for certain infectious diseases, for example, patients with diabetes mellitus type 2 have a threefold higher risk to developing tuberculosis (Riza et al. 2014) and there is some evidence that diabetes may increase the risk of malaria (Danquah et al. 2010). Thirdly, certain infectious diseases and some NCDs have shared risk factors (Oni and Unwin 2015) (Figure 2.1). Lastly, from a health system perspective, the requirements for the chronic care of HIV and NCD patients are similar, and it has been suggested that NCD control programs in LMICs should adopt care strategies that have worked well for HIV‐infected patients (Duffy et al. 2017). Both groups of patients need regular follow‐up to monitor effective­ ness of treatment, provide drug refills and reinforce health messages on adherence to medication and on risk reduction. Obviously, the growing number of patients with HIV‐NCD comorbidity is in itself a convincing reason to integrate both kinds of ser­ vices (Oni and Unwin 2015). Chronic kidney disease Tuberculosis

COPD

High BP

Malaria

Nutrition* Alcohol Tobacco

HIV

Urban/indoor air pollution

Diabetes Cerebrovascular disease Ischaemic heart disease

Socio-environmental^ Unsafe sex *Encompasses underweight, overweight/ obesity, low fruit/veg consumption, high glucase intake

Physical inactivity

^Conditions associated with informality: overcrowding, unsafe water & sanitation

Figure 2.1  Interaction between tuberculosis, malaria and HIV disease with risk factors/disease precursors and non‐communicable diseases. BP: blood pressure; COPD: chronic obstructive pulmonary disease. Source: This figure has been reproduced from the publication by Oni and Unwin (2015), which is an open access article distributed under the terms of CC BY‐NC‐ND. (See color plate section for the color representation of this figure.)

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2  The Burden of Non‐communicable Diseases in Low‐ and Middle‐Income Countries

2.6 ­The Health System Burden of NCDs Data on the burden of NCDs on specific health services are surprisingly limited, and only a few studies seem to have systematically investigated this important question. Given the high and growing prevalence of NCDs as observed in population‐based stud­ ies, one would expect that primary care facilities would face a huge NCD patient burden at all levels, from tertiary and district hospitals down to health centers and even to com­ munal health stations. However, in reality there are substantial and problematic dis­ crepancies between the patient load observed at hospitals and that seen at lower level facilities. For example, in the context of an NCD intervention programs conducted in East Africa, the health system burden of selected NCDs was studied in the outpatient depart­ ments (OPDs) of 52 health facilities in Uganda and Tanzania (8 hospitals, 20 health centers and 24 small primary care dispensaries). The observations across countries were very similar (Katende et al. 2015; Peck et al. 2014). Data are shown here for the study in Tanzania (Figure 2.2). As in many other LMICs, public health centers in East Africa serve a subdistrict with a population of about 20 000 people, and together with dispensaries, are the main point of call for patients with any health problem. Health centers are staffed with individuals with some clinical training and occasionally with doctors or assistant medical officers. Dispensaries have clinicians and nurses and serve a population of about 5000 individuals. In rural areas most patients with NCDs would be expected to  present at their local health facility, because this would save them time and money. However, this study from a representative sample of health facilities in north­ western Tanzania found that the mean number of outpatient visits related to chronic

Hospitals

Health centres

Dispensaries

1500

1000

500

Mean number of monthly visits HIV Hypertension

Diabetes Epilepsy

0

20

40

60

Proportion of all visits (%) Heart failure COPD/asthma

Figure 2.2  Burden of chronic diseases at 24 health facilities in northwest Tanzania. The mean number of chronic disease visits per month per facility is displayed to the left of the midline and the proportion of all outpatient visits due to chronic diseases is on the right. Data were collected from the adult outpatient departments of these 24 health facilities. COPD, chronic obstructive pulmonary disease. Source: This figure has been reproduced from the publication by Peck et al. (2014), which is an open access article distributed under the terms of CC BY‐NC‐ND. (See color plate section for the color representation of this figure.)

2.7  The Economic Impact of NCDs

diseases per month (including chronic HIV infection) was 1411 for hospitals, but only 44 for health centers, and 22 for dispensaries (Figure 2.2). Most outpatient services for NCDs were provided in hospitals instead of health centers and dispensaries. In fact, most dispensaries and half of health centers reported not providing services for common NCDs such as hypertension and diabetes, despite being expected to do so according to current policies, and instead routinely referred such patients to hospital. As a result, some hospital OPDs were overburdened by routine NCD cases whilst peripheral health facilities were underutilized. Obviously, targeted interventions are required to enable and encourage peripheral health facilities to provide routine out­ patient NCD services. The few available data on the utilization of NCD services from other LMICs show similar results. For example, a study from southern China showed that 75% of NCD patients presented at district or even tertiary hospitals (Yang et al. 2014), and hospital‐ based diabetes clinics reported a heavy NCD patient burden, as also shown in studies from Cameroon, Mali, Tanzania and South Africa (Brown et al. 2014).

2.7 ­The Economic Impact of NCDs 2.7.1  The Patient’s Perspective The essential medicines for the basic treatment of uncomplicated NCDs are compara­ tively inexpensive. The costs of a monthly supply of drugs for the treatment of hyper­ tension, diabetes or COPD are much lower than those, for example, of antiretroviral drugs. However, in LMICs where patients are often asked to pay for the medicines received or to share some of the costs, the expenditures for NCD medication over­ stretch the budget of the poor, whose average monthly cash income is at the poverty line of around US$1.25 per day, and this is particularly devastating in the elderly who often suffer from more than one NCD (Pati et al. 2014). Households respond to this pressure by reducing spending on food and education, and thus NCDs contribute to increasing impoverishment (Engelgau et al. 2011). When NCDs eventually lead to disabling or fatal complications, patients and their families face catastrophic healthcare expenditures (CHEs). CHEs are more common among NCD patients than among patients with non‐ chronic diseases (Si et al. 2017). CHEs due to NCDs have been observed in numerous LMICs and at various income levels, and for different groups has been reported by 6‐84% of the households studied (Jaspers et al. 2015). 2.7.2  The Provider’s Perspective From a healthcare provider point of view, expenditures for NCD case management comprise capital costs such as building use, equipment and staff training, and recurrent costs such as medicines and diagnostic consumables, staff time, general supplies and utilities (Settumba et al. 2015). Estimates of the costs per patient per year incurred for specific NCD care activities vary widely, depending on the country, medical condition, intensity of health service utilization, and on the underlying estimation methodology used (Brouwer et al. 2015). For example, in a systematic review of provider costs the annual expenditures per patient for basic hypertension outpatient care ranged from US$38 (Tanzania) to $566 (China), and those for basic diabetic care including oral

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2  The Burden of Non‐communicable Diseases in Low‐ and Middle‐Income Countries

metformin treatment from $77 (India) to $989 (China). The treatment costs for compli­ cations are substantially higher. For example, for stroke the costs per patient varied from $160 (Tanzania) to $1851 (Pakistan) and even reached $16993 (South Africa). Those for conservative diabetic foot care varied from $86 (India) to $1619 (Nigeria) (Brouwer et al. 2015). Given the high prevalence of NCDs in the general population of LMICs, healthcare expenditures are expected to rise massively, putting a huge and growing burden on health systems that continue to struggle with a high burden of com­ municable diseases as well (WHO 2011). 2.7.3  Macroeconomic Effects In 2011 at the request of WHO, in preparation for the United Nations Head of States’ meeting on NCDs, the Harvard School of Public Health and the World Economic Forum issued a report on the estimated macroeconomic impact of NCDs. The report stated that “NCDs already pose a substantial economic burden and this burden will evolve into a staggering one over the next two decades.” For example, with respect to cardiovascular disease, chronic respiratory disease, cancer, diabetes and mental health, the macroeconomic simulations suggested that there would be a cumulative output loss of US$47 trillion over the next two decades. This loss represented 75% of the global gross domestic product in 2010 (US$63 trillion) (Bloom et al. 2011). For LMICs this loss was calculated at US$21 trillion over the same period. Estimating the economic impact of diseases is not straight forward, and other authors have come to somewhat lower estimates (Abegunde et al. 2007; WHO 2014a). However, all agree that the economic loss is already huge, is expected to grow and will substan­ tially damage national economies. This is understandable because at the individual level over the coming years, as described above, NCDs are likely to push many more people below the poverty threshold and reduce their economic outlook. Because the burden of NCDs seems is rising quickly, it is expected that the economic loss will rise exponen­ tially (Bloom et al. 2011). It has also been estimated that compared to this economic impact, the costs of even a highly intensive worldwide NCD intervention program is small. The costs of such a program are thought to be in the order of US $10–12 billion per year (WHO 2014a). In other words, the costs of not intervening are expected to outweigh by far the costs for a thorough intervention program.

2.8 ­The Response to the NCD Epidemic in LMICs 2.8.1  Response at the International Level An increase in the prevalence of certain NCDs, in particular cardiovascular diseases and diabetes mellitus type 2, in low income countries was noted for some time before the end of the last century (Beevers and Prince 1991; King and Rewers 1993). However, only recently did the international community realize the size and importance of the growing NCD epidemic (Daar et al. 2007). In 2011 the issue was eventually brought to the attention of the United Nations General Assembly, and Heads of States recognized that NCDs presented a world‐wide “challenge of epidemic proportions” that was expected to grow particularly quickly in low and midlevel economies. A declaration was

2.8  The Response to the NCD Epidemic in LMICs

signed by all countries (UN 2011) in which Heads of States committed themselves to five action areas which included efforts to: (i) reduce NCD risk factors within popula­ tions; (ii) launch national NCD control policies and strengthen health systems in affected countries; (iii) collaborate internationally to better control NCDs; (iv) promote relevant research; and (v) to set and monitor measurable targets. WHO was tasked with developing detailed recommendations and providing technical guidance, overseen by a WHO Assistant Director‐General for NCDs and Mental Health. Subsequently in 2013 the UN formed the United Nations Interagency Task Force on NCDs (UNIATF). UNIATF’s role is to bring the different UN agencies together to address NCDs and to assist individual governments in the development of effective responses for the preven­ tion and control of NCDs (UNIATF 2017). UNIATF’s work is coordinated by WHO. Also, in 2013 WHO formulated a Global NCD Action Plan for the period which set nine targets including the aim of reducing NCD‐related mortality by 25% until the year 2025, and to ensure that at least 50% of NCD patients who require drug therapy should receive it (WHO 2013a). As part of this process and to strengthen primary healthcare services, a package of essential NCD control interventions (PEN) was published. This package is a useful tool for anybody responsible for the practical planning and implementation of NCD control activities in LMICs, and is available online (WHO 2013b). In 2014 the UN World Assembly reviewed the progress made, and noted that this has been rather limited and uneven across member states and that NCD control efforts should be intensified substantially (UN 2014). Member states then committed them­ selves to meet a list of specific time‐bound aims which were to be monitored by WHO (WHO 2017a). Further progress was to be reported to the General Assembly in 2018. Ten indicators were agreed. These stipulated that by 2018 at the latest, each member state should have established a multisectoral NCD control strategy, conducted surveil­ lance of NCD risk factors using the STEPwise approach to Surveillance (STEPS) instrument (WHO 2012), enforced comprehensive bans on tobacco and alcohol adver­ tising and introduced increased taxation, launched activities to improve dietary habits at the population level including a reduction in sodium consumption, and introduced primary care services for major NCDs using evidence‐based treatment protocols (WHO 2017a). 2.8.2  Response at the National Level Some limited progress has been made over recent years. Most LMICs adopted a national NCD control strategy, often combined with a written action plan. These pol­ icy documents describe the national control strategy and often provide useful infor­ mation on the importance of NCDs, the local epidemiology, and the various sectors that should play a role in the prevention and control of NCDs. For examples see Ministry of Health (MoH) Cambodia (2013), MoH Ghana (2012), MoH Trinidad and Tobago (2017). A few countries have introduced regular monitoring of the prevalence of NCD risk factors at the population level using serially conducted WHO STEPS surveys (WHO 2017b). The results of STEP surveys have been published as fact sheets, and these con­ firm that in the participating LMICs the prevalence of elevated blood pressure and blood glucose levels and of various NCD risk factors is indeed high. In countries that conducted serial STEPS surveys, an increase of risk factor prevalence over time has been documented.

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Some countries also evaluated the readiness of their healthcare systems to provide NCD care (for example, Nyarko et al. 2016), or started training programs to improve the awareness and skills of their primary care health workers (for example, Davila et al. 2015). However, overall little progress had been made on the ground: in 2015, based on self‐ reports from 177 national programs, including 80 from LIMCs, WHO stated that there was still a striking discrepancy between NCD control policies and plans, and their actual implementation, particularly in low income countries (WHO 2015). In most LMICs the response to NCDs was still limited to the health sector (rather than ensuring a multisectoral approach), there were few functioning NCD case finding activities, drug stocks for NCD treatments remained insufficient and budgets for NCD prevention and care were far too small to cope with the huge disease burden. A complicating factor is that the existing drug supply systems are administratively independent of NCD control programs and have not adapted swiftly to the increase in demand. Very few countries have managed to introduce the agreed ground‐breaking changes in tax legislation and advertising on alcohol and processed food. 2.8.3  Response by the Private Sector There have been encouraging developments in the private sector worldwide, both inter­ nationally and nationally, to address the NCD challenge. In 2009 several international agencies (including the International Diabetes Federation, the World Heart Federation and organizations engaged in responding to respiratory disease and cancer) formed a global partnership: the NCD Alliance. Over time, about 2000 local civil society‐based organizations joined this network. Activities include advocacy at international and national levels, and provision of assistance to local partners in terms of training and capacity building. In LMICs some Alliance members launched well‐coordinated pro­ grams assisting ministries of health with regards to training and capacity building. A good example is the Tanzanian Diabetes Foundation (TDA) which helped to establish integrated diabetes clinics in regional hospitals across the country. These clinics pro­ vide not just diabetes care but also NCD services in general. In collaboration with the Ministry of Health, the Foundation published case management and training guidelines that can be freely accessed on the internet (for example, TDA 2013, 2014). Similarly, the Global Initiative for Obstructive Lung Diseases (GOLD) was formed in 1998. This initiative aims to increase awareness and to monitor the epidemiology of COPD, and has issued carefully validated treatment guidelines (e.g. GOLD 2017b).

2.9 ­The Readiness of Primary Healthcare Services in LMICs to Cope with the NCD Burden In 2007 in an attempt to facilitate a common approach to the understanding and strengthening of health systems, WHO published a framework of six essential health systems’ building blocks (WHO 2007), all of which should function well in order to enable a health system to meet expectations. The six blocks are 1) health service delivery 2) the health workforce 3) health information systems

2.9  The Readiness of Primary Healthcare Services in LMICs to Cope with the NCD Burden

4) equitable access to medical products and technologies 5) health financing 6) governance Subsequently WHO issued a set of indicators to determine health systems functions, and a handbook describing how to collect data on these (WHO 2010a, b). To further facilitate data collection on these indicators, WHO published the Service Availability and Readiness Assessment (SARA) questionnaire, a set of comprehensive tools to sys­ tematically assess and monitor health services (WHO 2013c). The building block framework, the corresponding indicators and the SARA question­ naires are helpful tools for assessing the functionality of NCD control services, and these instruments are available online (WHO 2007, 2010a, b, 2013c). Furthermore, the SARA tool has been adapted to specifically evaluate NCD services at primary care facil­ ities including hospital outpatient services, and has been amended with an instrument to assess health workers’ knowledge on selected NCDs and, for comparison, on HIV infection (Peck et  al. 2014) including supplementary online material. Together these resources represent a useful arsenal of methods to assess NCD services and to plan interventions for their improvement. These validation methods have been applied to assess the functionality of NCD care at primary level in an NCD research program from East Africa (Katende et al. 2015; Peck et  al. 2014), and similar assessments have been conducted in a variety of other LMICs around the world (Mannava et al. 2015; Nyarko et al. 2016; O’Neill et al. 2013; Pakhare et al. 2015; Siddharthan et al. 2015; Van Minh et al. 2014; Wangchuk et al. 2014; Yassoub et al. 2014). The sobering overall result is that primary care services in most LMICs are not yet able to cope with the growing NCD burden: hospital outpatient departments (OPDs) of district and even tertiary hospitals are overwhelmed with an ever growing number of NCD patients, while health centers and other peripheral health facilities are bypassed and under­ utilized, mainly because they are not yet ready to manage routine NCD conditions. Most NCD patients could in principle be easily managed at smaller facilities: for example, uncomplicated cases of diabetes mellitus type 2 or chronic hypertension do not require specialist care. Strengthening peripheral facilities would go a long way to alleviate the burden of NCD care at hospitals, whilst saving time and travel costs incurred by patients. However, this is not happening for a number of reasons: ●●

●●

Historically, all levels of healthcare in LMICs had a focus on the management of acute infectious diseases such as malaria, diarrhea and respiratory tract infections, and the prevention and care of NCDs seemed of little importance. Health services in LMICs were not designed to deal with chronic conditions (Beaglehole et al. 2008). Most health workers are not trained to manage NCDs, the local logistics required to ensure a regular drug supply have not been developed, and the systems necessary to monitor patients with chronic diseases are not in place. This could have changed after the wide‐scale introduction of ART, which turned the previously fatal HIV/AIDS dis­ ease into a chronic treatable illness. From an organizational point of view, the primary care management of NCDs is similar to that of HIV infection in many regards, and so NCD services could have learned from those effective for HIV care (Harries et  al. 2009). Unfortunately, the influence HIV care programs have had on routine o ­ utpatient services has been limited because the response to the HIV epidemic was, for under­ standable reasons, driven by vertical programs, and so routine NCD services did not

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benefit from this development. Still, there is an opportunity here to learn from HIV care services, and both kind of services would benefit, given that many HIV patients face a high risk of developing NCDs (Duffy et al. 2017). There are other problems too: reliable data to assess the preparedness, quality and effectiveness of current NCD services are largely missing, and so it remains difficult to plan for effective NCD control measures (Ali et al. 2013). This resulted in a vicious cycle in which the absence of planning data and an inadequate response at the primary care level reinforced each other, thus perpetuating the problem. Whilst many countries have national NCD control policies by now, information about them has usually not reached the health services on the ground (Peck et al. 2013; Van Minh et al. 2014). Finally, simple case management guidelines are usually not in place. A multitude of NCD drugs are mentioned in some national essential drug lists, but health workers are not used to most of them, and drugs are frequently out of stock. Standardized case management algorithms currently in use (for example, control programs for sexually transmitted diseases (Garcia et al. 2012), have yet to be introduced for NCDs. Even the most essential diagnostic equipment such as sphygmomanometers, weighing scales, or glucometers are often not available (Katende et al. 2015; Peck et al. 2014).

2.10 ­Introducing Effective NCD Control at Primary Care Services: A Practical Approach Whilst NCD control in LMICs requires a multi‐sector response, its success will hinge hugely on the effective and widespread introduction of NCD services at the primary healthcare level. Given the complex challenges described above, a combination of coor­ dinated interventions is required to overcome them. Any program aiming to improve NCD prevention, detection and care will need to strengthen primary care services using a holistic approach that should include the 10 components described below. 2.10.1  Raising NCD Awareness Within the Health Services Many health program managers at provincial and district levels are not yet aware of the rapidly growing NCD problem, and consequently do not feel that NCDs have become a priority. NCD programs would therefore benefit from awareness and advocacy activi­ ties. These could consist of brief workshops organized for health service leaders, organ­ ized, for example, at a provincial level. There are useful brochures available that could be shared on such occasions such as those produced by WHO (2017c). Similarly, fact sheets from national STEPS surveys could help provide information about the situation within a specific country. Finally, both health program managers and all staff who pro­ vide OPD NCD care should be made aware of their country’s national NCD control policy, if this already exists. 2.10.2  Training Healthcare Workers A variety of approaches have been used, differing with regards to what topics should be covered, how many days such training should take and which health worker cadres

2.10  Introducing Effective NCD Control at Primary Care Services: A Practical Approach

should be included. In our experience from an NCD program in East Africa, it has been helpful to initially focus on the diagnosis and management of the most common NCDs rather than to strive for completeness. A five day training course is sufficient to teach the most important principles of diagnostic and case management procedures. Classroom‐ based teaching should be combined with some practical training delivered by experi­ enced trainers and clinicians utilizing the opportunity of a hospital OPD NCD clinic. The training should be as interactive as possible and cover at least the following topics: ●● ●● ●● ●● ●● ●● ●● ●● ●●

the growing burden of NCDs in LMICs the most common clinical conditions typical long‐term complications NCD diagnosis standard treatment algorithms referral guidelines case detection strategies simple record keeping practical exercises on health education for both individual patients and in the outpa­ tient waiting area

An example of a basic NCD training course timetable is available on the Internet and is shown in Figure 2.3. An example of a Clinic‐held NCD patient file is shown in Figure 2.4. Naturally, medical doctors and experienced clinical officers at hospital OPD services have found it helpful to expose such staff members to the same training as provided to lower cadres or those based at peripheral health centers. The aim is to make hospital doctors aware of newly introduced standardized NCD case management procedures and to ensure that they understand the knowledge and skills now available at lower levels of healthcare providers, which would still refer to them any complicated cases, and to which they should refer patients back once stabilized. It is important during the training to emphasize that NCDs such as diabetes, hyper­ tension or COPD can often be successfully treated without drugs if patients can be persuaded to follow advice on life style and nutrition. Health workers have a strong tendency to immediately prescribe medicines and to spend little time on health educa­ tion. Learning to give convincing life style advice requires special attention during the training course, and should be practiced, for example, using role playing. 2.10.3  Conducting Support Supervision The most important component of health workers’ NCD training actually happens after completion of the initial course. It is essential that within days after the course, health workers will be visited within their own working environment by a supervisor in order to reinforce what they have learned. Ideally this should be done by one of the course trainers. Diagnostic and therapeutic procedures are rehearsed, difficult cases discussed, and clinical records jointly reviewed. If possible, some NCD patients should be jointly attended to. Without this support health workers are likely to forget what they learned during the course. Note that just one such support visit is not sufficient; we recommend repeating it initially at monthly intervals, and later at least four times per year. A visit roster should be agreed and adhered to.

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2  The Burden of Non‐communicable Diseases in Low‐ and Middle‐Income Countries

Figure 2.3 below illustrates the following: 1. 2. 3. 4. 5.

NCD training course timetable Checklist for support supervision Clinic-held NCD patient file form Patient-held NCD card Scoring sheets for the evaluation of NCD services at primary care facilities

1. NCD training course for primary care health workers NCD Course Timetable Adapted from training courses held by the East African Chronic Disease Programme 2013 – 2017 Time

Content

Day 1 08.30 – 09.00

Session 1: Aims, objectives and course schedule

09.00 – 09.30

Session 2: Assessment of students’ current knowledge on chronic diseases

09.30 – 10.00

Session 3: How to use the training materials provided

10.00 – 10.30

Session 4: Introduction to non-communicable diseases (part 1)

10.30 – 11.00

Refreshments

11.00 – 11.30

Session 5: Introduction to non-communicable diseases (part 2)

11.30 – 12.15

Session 6: What is diabetes mellitus? What are its complications?

12.15 – 13.00

Session 7: How can diabetes mellitus type-2 be prevented?

13.00 – 14.00

Lunch Break

14.00 – 14.30

Session 8: Diagnosis of diabetes mellitus

14.30 – 15.30

Session 9: Non-pharmacological management of diabetes type 2 (How to educate patients and family members; with role playing)

15.30 – 15.50

Refreshments

15.50 – 16.20

Session 10: Pharmacologic management of non-insulin dependent diabetes mellitus

16.20 – 17.00

Session 11: 1. Summary and review of day 1 material: key issues to remember 2. Review of day 1 impressions and questions

Day 2 08:30 – 09.15

Session 12: Review of day 1: what did we learn?

09.15 – 09.45

Session 13: Case management flow chart for diabetes mellitus

09.45 – 10.30

Session 14: What is hypertension? What are its complications?

10.30 – 11.00

Refreshments

11.00 – 11.30

Session 15: How can hypertension be prevented?

11:30 – 12:00

Session 16: Diagnosis of hypertension

12:00 – 13:00

Session 17: Non-pharmacological management of hypertension (How to educate patients and family members; with role playing)

Figure 2.3  Non-communicable disease (NCD) training course  (Continued)

2.10  Introducing Effective NCD Control at Primary Care Services: A Practical Approach

13.00 – 14.00

Lunch Break

14.00 – 14.45

Session 18: Pharmacological management of hypertension

14.45 – 15.30

Session 19: Case management flow chart for hypertension

15.30 – 15.50

Refreshments

15.50 – 16.20

Session 20: Follow-up of patients with hypertension and diabetes mellitus

16.20 – 17.00

Session 21: 1. Summary and review of day 2 material: key issues to remember 2. Review of day 2 impressions and questions

Day 3 08:30 – 09.00

Session 22: Review of day 2: what did we learn?

09.00 – 09.45

Session 23: Recording and reporting: how to use clinic-held patient files, patient cards and referral forms (part 1)

09.45 – 10.30

Session 24: Recording and reporting: how to use clinic-held patient files, patient cards and referral forms (part 2), with practical exercises

10:30 – 11.00

Refreshments

11.00 – 12.00

Session 25: How to educate patients waiting in the OPD area (with role playing)

12.00 – 12.30

Session 26: Case detection of hypertension (HT) and diabetes (DM) patients and of patients with HT/DM risk factors: how to screen patients

12.30 – 13.00

Session 27: Review of hypertension and diabetes: diagnosis and treatment flow charts

13.00 – 14.00

Lunch break

14.00 – 14.45

Session 28: What is chronic obstructive pulmonary disease (COPD)? What are its complications?

14.45 – 15.30

Session 29: What is asthma? How to distinguish it from COPD? What are its complications?

15.30 – 15.50

Refreshments

15.50 – 16.40

Session 30: Diagnosis of COPD and asthma

16.40 – 17.00

Session 31: 1. Summary and review of day 3 material: key issues to remember 2. Review of day 3 impressions and questions

Day 4 08:30 – 09.00

Session 32: Review of day 3: what did we learn?

09.00 – 10.00

Session 33: Non-pharmacological management of COPD (How to educate patients and family members; with role playing)

10.00 – 10.30

Session 34: Pharmacological management of COPD

10:30 – 11.00

Refreshments

11.00 – 11.30

Session 35: Pharmacological management of asthma

11.30 – 12.00

Session 36: Case management flowchart for COPD and asthma

12.00 – 12.30

Session 37: Follow-up of patients with COPD and asthma

12.30 – 13.00

Session 38: Common cancers: overview

Figure 2.3 (Continued)

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2  The Burden of Non‐communicable Diseases in Low‐ and Middle‐Income Countries

13.00 – 1400

Lunch break

14.00 – 14.45

Session 39: The role of primary care health facilities in cancer detection

14.45 – 15.30

Session 40: The role of primary care health facilities in cancer prevention

15.30 – 15.50

Refreshments

15.50 – 16.30

Session 41: How to promote linkage to care, retention and adherence

16.30 – 17.00

Session 42: 1. Summary and review of day 4 material: key issues to remember 2. Review of day 3 impressions and questions

Day 5 08:30 – 09.00

Session 43: Review of day 4: what did we learn?

09.00 – 09.30

Session 44: Review of COPD/asthma flow chart

09.30 – 10.00

Session 45: Review of NCD diagnosis and management

10.00 – 10.30

Session 46: Review of NCD case detection

10:30 – 11.00

Refreshments

11.00 – 11.45

Session 47: How to integrate NCD education and case detection into mobile outreach activities

11.45 – 12.30

Session 48: Post test

12.30 – 13.30

Lunch break

13.30 – 16.00

Practical: Visit OPD services at selected primary care centres

Day 6 08:30 – 13.00

Practical: Visit OPD services at selected primary care centres

13.00 – 14.00

Lunch break

14.00 – 15.30

Session 49: Discussion of cases seen

Day 7 08:30 – 13.00

Practical: Visit OPD services at selected primary care centres

13.00 – 14.00

Lunch break

14.00 – 15.30

Session 50: Discussion of cases seen

15.30 – 15.50

Refreshments

15.50 – 16.20

Session 51: Preparation of 1st supervisory support visit (to be conducted within 2 weeks after the end of the training course): timing, logistics, expectations

16.20 – 16.50

Session 52: Course evaluation: participants’ feedback (in writing and by discussion)

16.50 – 17.00

Closing of training course

Figure 2.3 (Continued)

2.10  Introducing Effective NCD Control at Primary Care Services: A Practical Approach

2.

Checklist for support supervision visits

Health Facility______________________________________Health Facility Code___________ Names of Supervisor(s) __________________________________________________________ Date _____________________ Date of last supervision visit _____________________

1.

Staff

1

2.

●

Number trained in CD

●

Number who still work at this facility

●

Number available/present at HF at time of visit

●

Describe any additional staffing problems +/- suggested solutions

Treatment guidelines and tools ●

Is the desk guide for management of hypertension and diabetes available and in use at the HF?

(1 = available and in use, 2 = available but not in use, 3 = not available) ●

Is the algorithm for management of diabetes available and in use at at the HF?

(1 = available and in use, 2 = available but not in use, 3 = not available) ●

Is the algorithm for management of hypertension available and in use at the HF?

(1 = available and in use, 2 = available but not in use, 3 = not available) ●

Is the chart for interpreting body mass index (BMI) available and in use at the HF?

(1 = available and in use, 2 = available but not in use, 3 = not available) ●

Is the patient education information leaflet available and in use at the HF?

(1 = available and in use, 2 = available but not in use, 3 = not available) Figure 2.3 (Continued)

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2  The Burden of Non‐communicable Diseases in Low‐ and Middle‐Income Countries ●

3.

4.

5.

Use the space below to describe any additional problems with treatment guidelines

Case detection of NCDs ●

Is screening for HT/DM being done routinely at the OPD? (Y/N)

●

Is the screening register being used appropriately (Y/N)

●

How many patients have been screened since the last visit?

●

Describe below any additional problems with screening activities

Management of NCDs ●

Does the treatment for diabetes follow the guidelines? (Y/N)

●

Does the treatment for hypertension follow the guidelines? (Y/N)

●

Please describe below any additional problems with the treatment

Referral of patients

Examine the referral documents to ascertain the following points: ●

How many patients have been referred since the last visit?

●

List below the health facilities where the patients were referred to.

●

How many patients have been back-referred?

●

List below the facilities which referred patients back to this facility.

Figure 2.3 (Continued)

2.10  Introducing Effective NCD Control at Primary Care Services: A Practical Approach

6.

●

How many referrals did this facility receive from elsewhere?

●

List the health facilities from which patients were referred.

●

How many patients were referred back from here?

●

Provide any additional information on problems related to referrals

Essential medicines ●

Availability and supply

Medicine

Physically in stock today? (Y/N)

Usually in stock? (Y/N)

Date of last supply

Metformin Glibenclamide Insulin Bendrofluazide Nifedipine Atenolol

●

Describe any problems and proposed solutions:

Figure 2.3 (Continued)

Source of last supply: 1=NMS, 2=Project, 3=Other

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2  The Burden of Non‐communicable Diseases in Low‐ and Middle‐Income Countries 7.

Essential equipment ●

Availability and use of equipment

Equipment

Is equipment from project still present? (1=available and in use, 2=available but not in use, 3=not available)

Does the facility have alternative equipment? (1=available and in use, 2=available but not in use, 3=not available)

Measuring tape Weighing scale Stadiometer (for measuring height) Glucometer Blood pressure machine ●

8.

Describe any problems and proposed solutions:

Documentation and Monitoring ●

Are tools/forms available and in use? Are they being used appropriately?

Tool/Form

Screening register Patient-held cards Facility-held patient files NCD register Appointment book Referral form Figure 2.3 (Continued)

Available and in use? (1=available and in use, 2=available but not in use, 3=not available) If 2, or 3 discuss with staff and summarise discussion (problems and solutions) below

Being used appropriately? (Y/N) If No, discuss with staff and summarise problems and solutions below

2.10  Introducing Effective NCD Control at Primary Care Services: A Practical Approach ●

9.

10.

Describe any problems and proposed solutions:

Community outreach ●

Does this facility conduct any community outreach activities? (Y/N)

●

Please describe any activities conducted since last support visit:

●

How frequently have these activities been performed?

Utilization of facility

●

Number of new patients registered with diabetes

●

Number of diabetes patients seen for follow-up (FU)

●

Number of new patients registered with hypertension

●

Number of hypertension patients seen for FU

●

Number of other NCD patients newly registered

●

Number of NCD health education sessions held

11.

Patient-held card

Front page Figure 2.3 (Continued)

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2  The Burden of Non‐communicable Diseases in Low‐ and Middle‐Income Countries

NCD PATIENT ID CARD for presentation at health facilities Health facility name: ……….......................... Patient number: .......................................... Patient name: ……….………………………………………… Age: ……………years

Sex: M / F

Address: ……………………………………………… Telephone: ……………………………………… Diagnoses: (please underline) Diabetes | Hypertension | COPD | Other If other, specify Overleaf Date of appointment

Current treatment

Figure 2.3 (Continued)

These supervisory visits also provide an excellent opportunity to monitor the opera­ tional performance of NCD services, and to address problems that are likely to emerge over time. For this purpose, supervisors should use standardized checklists that allow a regular review of key functions and collection of essential data. As indicated above, this information should include: ●● ●● ●● ●● ●● ●● ●●

the presence and functionality of equipment the availability of essential drugs health workers’ adherence to treatment guidelines and algorithms the number and diagnoses of NCD patients registered the conduct of case detection activities the number of patients referred and back‐referred the number of patients reached through health education sessions in OPD waiting areas.

Any outreach activities should also be monitored with respect to NCD services pro­ vided, new cases detected and educational sessions conducted. The information col­ lected can be compiled at a central level and used for the evaluation of the program. Figure 2.4 shows an example of a clinic-held NCD patient file.

Symptoms / Complications

Wt (kg)

BMI

Waist

Hip

BP

Blood glucose

DOB:

Urine

Ketones

Education Given?

(Current medication; side effects if any)

TREATMENT SPECIFICS

Phone:

Relationship:

Treatment supporter:

Date of 1st visit:

(Details)

LIFE STYLE ADVICE GIVEN

Date agreed for next visit

Complications: A, none; B, blood glucose > 10mmol/L; C, hyperosmolar coma; D, ketoacidosis; E, hypoglycemia; F, foot infection / ulcers; G, neuropathy, extremity numbness/pain; H, erectile dysfunction; I, cataract; J, retinopathy; K, nephropathy / proteinuria

Date Attended

Height:

Diagnoses:

District:

Clinic number:

Phone:

Ward:

Fasting

Sex:

Random

Patient address:

Glucose

Health facility:

Proteins

Page: ……..

Disease Education

Patient number: ……………………

Lifestyle advice

Patient name: ………………..

Education leaflet used?

Figure 2.4  Clinic‐held NCD patient file

64

2  The Burden of Non‐communicable Diseases in Low‐ and Middle‐Income Countries

Who should perform these support supervision visits? This is ideally done by district level staff, although hospital‐based supervision services also exist in some places. There are similarities here with the district tuberculosis control or the district AIDS control programs, which are in place in many countries. District medical officers should nomi­ nate NCD coordinators who will be responsible for training, supervision and monitor­ ing of NCD control activities. It is important that the right staff members are identified for such tasks. NCD coordinators should typically be experienced clinical officers who have managerial skills and an enthusiastic interest in public health. 2.10.4  Providing Essential Diagnostic Equipment and Tests These should focus on the most common NCDs. The minimum equipment required at peripheral health facilities include a sphygmomanometer with different cuff sizes to measure blood pressure, a glucometer with a reliable supply of strips to determine blood sugar levels, a stethoscope for the auscultation of the heart and lungs, and a tape measure to measure waist circumference for the documentation and monitoring of overweight patients, and of those with metabolic syndrome. Instead of the tape meas­ ure, a weighing scale, stadiometer and a body mass index (BMI) calculation chart are often preferred. The diagnosis of COPD can be made using a simple handheld respirom­ eter after application of a short‐acting bronchodilator. Visual acuity can be tested in diabetes patients with suspected retinopathy using a Snellen chart. Standard dipstick strips can be used to detect proteinuria when diabetic kidney disease is suspected. At district hospital OPDs, an HbA1c blood test to determine antidiabetic treatment effi­ cacy, a urine test for microalbuminuria, and a hand‐held ophthalmoscope for the diag­ nosis of retinopathy should be available. 2.10.5  Ensuring a Reliable Supply of Essential NCD Drugs A huge number of drugs can be found in national ‘essential’ drug lists in some LMICs, often reflecting the preference that different specialists may historically have had when these lists were developed. For the routine care of most NCD patients only a few types of medicines are needed, and low‐cost generic drugs should be obtained for this purpose. The first line drug treatment of hypertension requires a thiazide (for example, ben­ drofluazide or hydrochlorothiazide). If an additional drug is required, a calcium chan­ nel blocker (for example, nifedipine), an acetyl choline esterase (ACE) inhibitor (for example, lisinopril) or a β‐blocker (for example, atenolol) can be added. For diabetic patients a biguanide (metformin) is required, which can if necessary be combined with a drug from the sulfonylurea group (for example, glibenclamide). Patients that require insulin injections should initially be managed at a hospital or a diabetes clinic, but once stable may be monitored at peripheral health facilities close to their home. The list of medicines for COPD at the primary care level should include a short‐­acting inhaled β2‐agonist (for example, salbutamol) and/or an inhaled acetylcholine blocker (for example, ipratropium), plus an oral methylxanthine (for example, aminophylline) if nec­ essary. Patients with acute exacerbations of COPD may require an inhaled β2‐agonist and short‐term oral glucocorticosteroids (for example, prednisolone), and possibly a broad‐ spectrum antibiotic treatment (Ait‐Khaled et al. 2001; GOLD 2017a, b). Treatment with bronchodilators in nebulizers may be given at hospitals.

2.10  Introducing Effective NCD Control at Primary Care Services: A Practical Approach

2.10.6  Introducing Standardized NCD Case Management Algorithms Most cases of uncomplicated NCDs can be managed with life style adaptation and a small selection of inexpensive drugs that are applied according to simple standardized treatment guidelines. These guidelines can be condensed into treatment algorithms that should be available in each OPD consultation room. Such standardized algorithms are based on easy‐to‐follow diagnostic steps and treatment principles, and are an essen­ tial tool for any NCD control program (Figure  2.5). Treatment algorithms should be accompanied by a more detailed desk guide so that health workers can look for addi­ tional guidance if needed. Examples of NCD desk guides can be found on the internet, for example, TDA (2013). 2.10.7  Treating Patients Close to Their Residence: Effective Referral and Back‐referral A major challenge for NCD patients is the frequent lack of treatment opportunities within their community, particularly in rural areas, and this is a major problem for both linkage and adherence to care. Consequently, patients remain either untreated or often DIABETES MELLITUS TREATMENT ALGORITHM at health center level (for non-insulin dependent diabetes) Diagnose Diabetes. Give lifestyle and dietary advice

Control is achieved if: RBG < 15 mmol/L or FBG < 11 mmol/L

If acute complications, refer to District Hospital! Yes

FU in 1 month Controlled?

Metformin 500mg PO BD + Continue trmt. Follow-up (FU) in 3 months

Yes

FU in 1 month Controlled?

Metformin 1000mg PO BD + Yes

FU in 1 month Controlled?

Refer to District Hospital *Intensive counseling on lifestyle and drug adherence MITU, Tanzania 2013

Figure 2.5  An example of a treatment algorithm for diabetes mellitus used in primary care facilities in an NCD control project from a resource‐restricted setting in East Africa.

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2  The Burden of Non‐communicable Diseases in Low‐ and Middle‐Income Countries

interrupt their medication, and in any event have a high risk of long‐term complica­ tions. Those that do link to care face travel costs and loss of income whilst away. A major objective of NCD control programs is therefore to strengthen peripheral health facili­ ties so that they can provide essential services close to patients’ area of residence. The referral of patients to higher levels of care should be reserved for those with complica­ tions or who are difficult to treat. Importantly, care providers at hospitals must back‐ refer patients once they are stabilized. This in turn requires some cooperation between the facilities involved, including communication by brief but comprehensive referral and back‐referral notes, ideally using a standard form. This need for an effective col­ laboration between smaller peripheral health facilities and the hospital NCD clinic is a good reason to include staff from both levels of healthcare in the same NCD training program. An alternative strategy to ensuring user‐friendly NCD services is the allocation of dedicated community nurses who regularly contact patients at or near their homes to  monitor their health, provide drug refills and conduct a brief examination. Observations are recorded using a brief standardized checklist. If anything unusual is observed, the nurse will contact a facility‐based clinician by mobile phone to seek advice. If necessary, the patient is sent to hospital for further examination. This approach has been successfully implemented, for example, in a NCD control program in South Africa (Coleman et al. 1998). A similar strategy has been used for the chronic care of HIV patients on ART in Uganda. Interestingly, such models compare favorably with purely facility‐based care both in terms of clinical effectiveness and costs (Jaffar et al. 2009). 2.10.8  Introducing Health Education and NCD Case Detection The majority of NCD patients are not aware of their condition (Beagley et  al. 2014; Hendriks et al. 2012; Kavishe et al. 2015), and are usually first seen at health services once they develop complications which are often lethal. For example, a recent analysis of inpatient records from a large tertiary hospital in northern Tanzania revealed that hypertension has become the second most common cause of mortality among patients admitted to a medical ward, surpassed only by HIV disease (Peck et al. 2013). Yet almost all such cases could in principle be prevented, provided that they were detected early. It is of great public health importance that routine primary care services make a major effort to identify patients with undetected NCDs as early as possible and ensure that they are monitored and receive adequate treatment. Our own experience with the introduction of screening services at general OPD clin­ ics both at hospitals and smaller health facilities has been encouraging. Patients waiting for consultation for any kind of ailment were invited to listen to a health talk on com­ mon NCDs. Afterwards all were offered to have their blood pressure measured. Individuals aged 40 years and above, those who were obviously overweight and anybody with a family history of diabetes were screened for an elevated random blood glucose level. Patients with suspected hypertension or diabetes were then asked to return for a confirmatory investigation on a subsequent day. For people with suspected diabetes this included a fasting blood glucose test. A similar strategy was applied at antenatal clinics. With his approach large numbers of individuals were screened, and many unknown NCD cases detected and subsequently followed up.

2.11  The Role of Primary Healthcare Services in Cancer Prevention and Care

2.10.9  Establishing an Effective Recording System Keeping carefully completed patient records is essential for all patients attending a health facility, but even more so for NCD patients, as they will be in contact with the health system many times, possibly lifelong, and previous records are needed to see whether a chronic condition improves or worsens. Unfortunately, health workers are already burdened with much paper work, so keeping records brief and simple is impor­ tant. The widespread system in LMIC primary care facilities of recording subsequent patients in large ledger books is not really helpful as with this system it is always difficult to trace previous entries. The problem can be solved by learning from HIV care programs which introduced individual clinic‐held patient files, marked with the name of the patient or a unique individual number. The minimum set of data to be monitored and recorded at the con­ sultation visit should include the name, gender, age, diagnosis, date of last visit, clinical information at each visit (blood pressure, blood sugar level, etc.), current symptoms and current treatment. Patients themselves can be provided with a small card with identify­ ing information, diagnoses and current treatment. The card enables rapid identification of the respective clinic‐held patient file and is also helpful if the patient presents to a different clinic. Examples of a standard clinic‐held patient NCD file and of a patient‐ held NCD card are available online (see Figures 2.3 and 2.4) 2.10.10  Integrating NCD Control Measures into Outreach Activities Many health facilities regularly reach out to the community, for example, for vaccina­ tion or antenatal services. On these occasions they often collaborate with community health workers or local village health teams. Such outreach activities offer a unique opportunity to also conduct public information campaigns on NCDs. The objective is to raise awareness on NCDs in the general population and to address erroneous beliefs and myths, but also to integrate case detection and treatment into other ongoing ser­ vices. The concept of NCDs is still alien to many people, including the need to make life style changes for primary or secondary NCD prevention, or for long‐term treat­ ment. Misconceptions are frequent and include beliefs that NCDs result from ill‐ intended supernatural influences, or that modern medicines are ineffective or even harmful. Not uncommonly NCD patients even experience stigmatization (Nnko et al. 2015). It is therefore important to use such outreach activities to educate the general public on NCDs.

2.11 ­The Role of Primary Healthcare Services in Cancer Prevention and Care The effective management of cancers requires specialist skills and is costly. Most LMICs have only a few national centers that provide such services. Unfortunately, can­ cer patients often present at a late stage, and the mortality of cancer in LMICs is high. For patients and their families, most cancer diagnoses represent a disaster, resulting in  catastrophic healthcare expenditures and poverty (ASEAN Cancer Action Study Group 2017).

67

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2  The Burden of Non‐communicable Diseases in Low‐ and Middle‐Income Countries

Yet for some common cancers, primary healthcare services can play an important role in prevention or early detection. Among women one of the most frequent tumors is cancer of the uterine cervix. In high income countries screening for the detection of early cancerous lesions is per­ formed using cytology or human papilloma virus (HPV) tests. In LMICs these are not routinely available. However, a simple and reasonably effective alternative screening strategy is the visual inspection with acetic acid (VIA) or Lugol’s iodine (VILI) applied during a speculum examination of the cervix. The technique is inexpensive and does not require much training (Fokom‐Domgue et al. 2015). It can be applied by nurse mid­ wives at primary care clinics provided women are made aware that such service is locally available. Women with a positive screening result are then referred for gyneco­ logical treatment. It is incomprehensible that this simple and low‐cost screening strat­ egy has not yet been widely introduced in LMICs. Cervical cancer can be reliably prevented by vaccination against infection with high‐ risk strains of the HPV (WHO 2014b). HPV vaccination is currently being introduced in many LMICs (Gallagher et  al. 2017), and once this is well established it can be expected that primary care services will play a pivotal role in achieving wide coverage by vaccinating adolescent girls. Two doses are recommended, given six months apart, but a three‐dose schedule is also in use. Similarly, a large proportion of liver cancers can be prevented through vaccination against hepatitis B virus infection (Nelson, Easterboork and McMahorn 2016). This vaccine is given at birth, and three further doses are provided jointly with routine DPT vaccinations. Since the onset of the AIDS epidemic, Kaposi’s sarcoma has become another very common cancer in LMICs, affecting men and women at a young age (Forman and Ferlay 2014). Facility or home‐based HIV counseling and testing provided through primary care services can help to diagnose HIV infection early, and to initiate ART before the patient’s immune system is seriously damaged (Ruzagira et  al. 2017). Effective ART treatment prevents HIV disease progression and reliably reduces the risk of developing Kaposi’s sarcoma (Bohlius et al. 2014). In addition, once primary care health workers have adopted the basic principles of care for common non‐cancerous NCDs, they can also be trained in the recognition of symptoms and signs that are suggestive of cancers of the breast, skin, prostate and the intestinal tract. The health workers’ role will then be to refer patients with such symp­ toms to specialist care as early as possible. Promising research is underway toward the development of technologies for the diagnosis and treatment of cancers in LMICs, including early cancer diagnosis at primary care facilities (Pearlman et al. 2016).

Figure 2.6  (a) Evaluation of NCD services at 75 primary care facilities in Uganda and Tanzania that participated in an NCD intervention trial. The figure shows facility performance scores (0–100) averaged over intervention and control units, by country. The score is a composite measure of NCD service availability and readiness including health workers’ knowledge. (b) Evaluation of NCD services at 75 primary care facilities in Uganda and Tanzania that participated in an NCD intervention trial. The figure shows the proportion of NCD patients adequately managed, by country and health facility type. The assessment was based on a composite measure to determine the quality of NCD care received by a total of 300 individual patients.

2.11  The Role of Primary Healthcare Services in Cancer Prevention and Care

Average NCD care readiness level achieved by health facilities, using a set of predefined standard indicators

100

Intervention Control

90 80 70 60 50 40 30 20 10 0

Small health centres (dispensaries)

Larger health centres

Tanzania

Percentage of NCD patients who were adequately managed, using a set of predefined standard indicators

100

Small health centres (dispensaries)

Larger health centres

Uganda

Intervention Control

90 80 70 60 50 40 30 20 10 0

Small health centres (dispensaries) Tanzania

Larger health centres

Small health centres (dispensaries) Uganda

Larger health centres

69

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2  The Burden of Non‐communicable Diseases in Low‐ and Middle‐Income Countries

2.12 ­Evaluating Programmes to Strengthen NCD Services at Primary Care Level There are different strategies to evaluate the effectiveness of programs that aim to improve NCD services at primary care level. One option is to apply the WHO Service Availability and Readiness (SARA) tool (WHO 2013c). However, it would be ideal to measure the effectiveness of an intervention program in a quantifiable way that would also determine the quality of care actually provided to a selection of individual NCD patients. In an NCD intervention trial conducted at primary care facilities in East Africa with funding from the Medical Research Council UK and with material support from the TDA (Trial registration number ISRCTN27340385), the investigators designed a sys­ tem to evaluate two important aspects of NCD services: 1) Service readiness assessed by physical inspection, including health workers’ knowl­ edge on NCDs assessed through a knowledge test 2) Quality of care received by randomly selected patients, assessed through interviews, examination and evaluation of patient records. For each of these components, a scoring system was an a priori definition against which health facilities were evalu­ ated. Such assessment may be applied before and after the intervention, or, as in the case of this trial, through a randomized controlled design. Examples of the scoring sheets used in this NCD control project are available online (see Figures 2.3 and 2.4) The trial demonstrated that an affordable and sustainable intervention comprising the 10 intervention components described above can be highly effective in improving the response to NCDs at peripheral health facilities (manuscript submitted) (Figure 2.6a and b). The overall scores achieved in the intervention group of health facilities as compared to the control group, based on the physical readiness of services with respect to the availability of equipment, medicines, policies and guidelines and utilization of services and health workers’ knowledge on NCDs, increased from approximately 40/100 to more than 75/100, and the proportion of patients with hypertension or diabetes who were adequately managed more than quadrupled from approximately 20 to about 90%. The intervention was also cost‐effective when analyzing the costs per case adequately treated. Based on these encouraging results, the intervention has subsequently been extended to the control facilities.

2.13 ­Conclusions Non‐communicable diseases represent a major burden of disease in the LMICs. This is slowly being realized and methods are being put in place to diagnose and treat them early.

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Part II

How to Improve Healthcare in Low‐ and Middle‐Income Countries by Primary Point‐of‐Care Rapid Diagnostic Testing

“And my best friend, my doctor Won’t even say what it is I’ve got” From the song Just like Tom Thumb’s Blues by Bob Dylan, Nobel Laureate in Literature 2016, from his album Highway 61 Revisited issued in 1965.

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3 The Optimal Features of a Rapid Point-of-Care Diagnostic Test David Mabey and Rosanna Peeling London School of Hygiene and Tropical Medicine, London, UK

­CHAPTER MENU 3.1 3.2 3.3 3.4 3.5

Introduction, 83 Accuracy Versus Accessibility,  83 Quality Assurance,  84 The Importance of Connectivity,  85 Environmental Friendliness,  86 References, 86 Webliography, 87

3.1 ­Introduction Lack of access to quality diagnostic tests remains a major contributor to the health burden in resource‐limited settings. Point‐of‐care (POC) tests have the potential to reduce this burden by making high quality diagnostic tests available to populations that do not have access to laboratory tests. The optimal features of a POC diagnostic test can be summarized by the acronym ASSURED (Mabey et al. 2004). It should be Affordable, Sensitive, Specific, User‐friendly, Rapid and Robust, Equipment‐free and Deliverable to end‐users (Table 3.1). Although technological advances have led to the development of many excellent POC tests in recent years which fulfill these criteria, there is inevitably a trade‐off between them. A test which costs less than US$0.5, requires no equipment and gives a result in less than 30 minutes is likely to be less sensitive than a more expensive test requiring equipment and electricity, which gives a result in more than two to three hours.

3.2 ­Accuracy Versus Accessibility In deciding which is the optimal test to use in a given situation, it is important to bear in mind that a less sensitive POC test which is widely accessible may prevent more adverse health outcomes than a highly sensitive laboratory‐based test available only to a privileged few (Smit et al. 2013a). Revolutionizing Tropical Medicine: Point-of-Care Tests, New Imaging Technologies and Digital Health, First Edition. Edited by Kerry Atkinson and David Mabey. © 2019 John Wiley & Sons, Inc. Published 2019 by John Wiley & Sons, Inc.

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Table 3.1  The ASSURED criteria grouped into the 3 A’s of diagnostics. Criteria

Description

Category

A

Affordable

Affordability to end users and health systems

Affordability

S

Sensitive

Avoid false negatives

Accuracy

S

Specific

Avoid false positives

U

User‐friendly

Simple to perform in a few steps, minimal training, non‐ invasive specimens

R

Rapid and robust

Results allow treatment at same visit, tests remain robust through varying supply chain and storage conditions

E

Equipment free Least use of expensive equipment

D

Deliverable to end‐users

Access

Tests must be available and accessible to those who need them

Gift et al. (1999) have drawn attention to what they call the rapid test paradox, whereby a less sensitive POC test for Chlamydia trachomatis, which enables same‐day treatment, results in more infected people receiving treatment than a sensitive, laboratory‐based test which requires patients to make a second visit to receive their result and treatment. It is important for regulatory agencies, and those responsible for drafting target product profiles for diagnostic tests, to bear this in mind when approving or licensing new POC tests, and not to let the best be the enemy of the good. The World Health Organization (WHO) has taken this into account in developing target product profiles for POC syphilis tests, in which a minimal sensitivity of 80% compared to a laboratory‐based assay is considered acceptable. This would enable countries to make syphilis screening available to all women attending antenatal clinics (ANCs) and increase the proportion of pregnant women with syphilis identified in sub‐Saharan Africa, where approximately 90% of pregnant women attend an ANC at least once per pregnancy, from less than 50% to more than 70% (Figure 3.1)(WHO 2016; Wijesooriya et al. 2016).

3.3 ­Quality Assurance Ensuring the quality of both POC tests and that of testing performed at hundreds or thousands of different sites by healthcare workers, who are not skilled in reading test Access 100 90 80 70 60 50 40 30 20 10

100 100 90 80 70 60 50 40 30 20 10

Sensitivity 90 80 90 80 72 81 72 63 54 45 36 27 18 9

64 56 48 40 32 24 16 8

70 70 63 56 49 42 35 28 21 14 7

Figure 3.1  The trade‐off between access and sensitivity.

3.4  The Importance of Connectivity

results, is a major challenge (Nkengasong et al. 2016). Approaches to external quality assessment (EQA) for POC tests include the use of proficiency panels consisting of dried positive and negative samples provided to the POC testing sites as blinded panels, in order to determine if the healthcare workers can obtain the correct results. These dried tube samples do not require refrigeration and have been used in many remote settings including the Amazon region of Brazil (Benzaken et al. 2014). Ideally the results of EQA results from POC testing sites should be read electronically and reported automatically to a central database (Cheng et al. 2016). Another method of assuring quality consists of collection of a second sample at the point‐of‐care for re‐testing, using a “gold standard” test, at a central laboratory. Dry blood spots have been used in this way for EQA of syphilis testing in rural Tanzania (Smit et al. 2013b).

3.4 ­The Importance of Connectivity Electronic readers and smartphones have the potential to standardize the interpretation of POC tests. Many POC test manufacturers now incorporate connectivity into POC and near‐POC instruments. Alternatively, lateral flow tests can be scanned by a reader or a mobile phone, making it possible to link data from POC test readers and devices to Ministries of Health and thus provide critical information on testing coverage and disease trends (Wedderburn et al. 2015). The Ebola crisis demonstrated the importance of integrating digital technology with a new generation of POC molecular tests that are highly sensitive and specific. Digital technology helped facilitate and improve patient record management, clinical treatment of patients and quality monitoring. These advances can also form the basis of early warning systems to identify disease outbreaks and optimize control and elimination interventions, and can be used to support quality assurance programs. With the addition of barcodes, 2D codes, or electronic storage to the tests, other data can be collected by smartphones, including manufacturing information (for example, lot numbers) and dates, expiry dates, stock availability and possibly even environmental conditions such as temperature and humidity under which the tests have been manufactured, transported, stored and used (Figure 3.2).

1

Quality Assurance

2

Patient treatment

3

Public health monitoring

4

Outbreak response

5

Stock management

Figure 3.2  Connectivity not only turns data into intelligence but also enables improvement of the quality of testing, supply chain management and patient care.

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3  The Optimal Features of a Rapid Point-of-Care Diagnostic Test

3.5 ­Environmental Friendliness As more and more diagnostic tests are used in both urban and rural areas, there should be more effort devoted to mitigating the environmental impact of these tests. Although individual tests do not pose a significant risk, many thousands of tests performed at each site pose environmental risks. The plastics used in current rapid tests cannot be recycled and produce toxic fumes if burnt. Focus needs to be placed on the materials used for these tests, including the housing, substrate matrix materials and reagents used in the test. Paper is an obvious choice of substrate material and has many inherent advantages over standard plastic materials. There is currently a lot of activity in the field of micropaper‐based analytical devices (Cate et al. 2015; Martinez et al. 2010). Similar materials could be used for storage, making tests biodegradable or easily disposable. Additional factors that also need to be considered include materials used for active components such as electronic tracks and electrodes, and the disposal of samples.

References Benzaken, A.S., Bazzo, M.L., Galban, E. et al. (2014). External quality assurance with dried tube specimens (DTS) for point‐of‐care syphilis and HIV tests: experience in an indigenous populations screening programme in the Brazilian Amazon. Sex. Transm. Infect. 90 (1): 14–18. Cate, D.M., Adkins, J.A., Mettakoonpitak, J., and Henry, C.S. (2015). Recent developments in paper‐based microfluidic devices. Anal. Chem. 87: 19–41. Cheng, B., Cunningham, B., Boeras, D.I. et al. (2016). Data connectivity: a critical tool for external quality assessment. Afr. J. Lab. Med. 5 (2): 535. https://doi.org/10.4102/ajlm. v5i2.535. Gift, T.L., Pate, M.S., Hook, E.W. et al. (1999). The rapid test paradox: when fewer cases detected lead to more cases treated: a decision analysis of tests for Chlamydia trachomatis. Sex. Transm. Dis. 26: 241–242. Mabey, D., Peeling, R., Ustianowski, A., and Perkins, M. (2004). Diagnostics for the developing world. Nat. Rev. Microbiol. 2: 231–240. Martinez, A.W., Phillips, S.T., Whitesides, G.M., and Carrilho, E. (2010). Diagnostics for the developing world: microfluidic paper‐based analytical devices. Anal. Chem. 82: 3–10. Nkengasong, J., Boeras, D.I., Abimiku, A., and Peeling, R.W. (2016). Assuring the quality of diagnostic testing: the future is now. Afr. J. Lab. Med. 5 (2): a558. https://doi.org/10.4102/ ajlm.v5i2.558. Smit, P.W., Mabey, D., Changalucha, J. et al. (2013a). The trade‐off between accuracy and accessibility of syphilis screening assays. PLoS One 8 (9): e75327. https://doi.org/10.1371/ journal.pone.0075327. Smit, P.W., van der Vlis, T., Mabey, D. et al. (2013b). The development and validation of dried blood spots for external quality assurance of syphilis serology. BMC Infect. Dis. 13 (1): 102. Wedderburn, C.J., Murtagh, M., Toskin, I., and Peeling, R.W. (2015). Using electronic readers to monitor progress toward elimination of mother‐to‐child transmission of HIV and syphilis: an opinion piece. Int. J. Gynaecol. Obstet. 130 (Suppl 1): S81–S83. https:// doi.org/10.1016/j.ijgo.

Webliography

Wijesooriya, N.S., Rochat, R.W., Kam, M.L. et al. (2016). Global burden of maternal and congenital syphilis in 2008 and 2012: A health systems modelling study. Lancet Global Health. 4 (8): e525–e533. https://doi.org/10.1016/s2214‐109x(16)30135‐8. World Health Organisation. (2014). Sexually transmitted infections point‐of‐care testing, 06‐08 May 2014, Annecy, http://www.who.int/reproductivehealth/potc‐tpps‐2‐16.pdf

Webliography http://doi.org/10.4102/ajlm.v5i2.558. Nkengasong, J., Boeras, D.I., Abimiku, A., and Peeling, R.W. Assuring the quality of diagnostic testing: The future is now. Afr J Lab Med. 2016 5(2) a558 http://who.int/reproductivehealth/POTC‐TPPs‐2016.pdf?ua=1

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4 Revolutionizing HIV Healthcare Delivery Through Rapid and Point‐of‐Care Testing Catherine J. Wedderburn, Debrah I. Boeras, and Rosanna W. Peeling International Diagnostics Centre, Clinical Research Department, London School of Hygiene & Tropical Medicine, London, UK

CHAPTER MENU 4.1 Synopsis, 88 4.2 Introduction, 89 4.3 Diagnostic Tests in Resource‐Limited Settings,  89 4.3.1 Challenges of Healthcare Delivery in Resource‐Limited Settings,  89 4.3.2 Diagnostic Tests Needed to Reach the 90‐90‐90 Targets,  90 4.3.2.1 The First 90,  90 4.3.2.2 The Second 90,  92 4.3.2.3 The Third 90,  92 4.4 Challenges of Using Rapid and Point‐of‐Care (POC) Testing Within the Context of the Healthcare System,  92 4.5 Recent Advances in HIV Diagnosis and Monitoring and Their Impact,  93 4.5.1 HIV Self‐testing and Multiplex Testing,  93 4.5.2 Early Infant Diagnosis of HIV,  94 4.5.3 POC CD4 Testing for Managing HIV Patient Care,  96 4.5.3.1 Before the Initiation of ART,  96 4.5.3.2 The Use of the CD4 Test for Early HIV Disease,  96 4.5.3.3 The CD4 Test for Advanced HIV Disease,  97 4.5.4 POC HIV Viral Load Monitoring,  97 4.6 WHO Recommendations: POC Diagnostics for Achieving the 90‐90‐90 Goals,  98 4.7 Remaining Challenges – Human Resources, Quality Assurance, and Test Selection and Placement, 98 4.8 Moving Forward,  99 4.9 ­Conclusions,  100 Bibliography, 101 Webliography, 103

4.1 ­Synopsis A range of innovative rapid diagnostic tests are commercially available for increasing access to the serological diagnosis of human immunodeficiency virus (HIV) disease HIV‐1 and ‐2 in adults, virological diagnosis of HIV in infants born to seroposi­ tive  mothers, monitoring HIV viral load in patients on treatment, and CD4+T cell Revolutionizing Tropical Medicine: Point-of-Care Tests, New Imaging Technologies and Digital Health, First Edition. Edited by Kerry Atkinson and David Mabey. © 2019 John Wiley & Sons, Inc. Published 2019 by John Wiley & Sons, Inc.

4.3  Diagnostic Tests in Resource‐Limited Settings

enumeration for the management of advanced HIV disease. Studies have shown that point‐of‐care (POC) testing has the potential to expand testing coverage, enhance linkage to care, minimize loss to follow up and increase the efficiency of the healthcare system by reducing the number of patient visits and healthcare workload. Challenges include increased demands on training, quality assurance, and supply chain manage­ ment to cover all POC sites. Advances in POC diagnostic technologies can be lever­ aged to revolutionize healthcare delivery for HIV if they are implemented within a connected diagnostic system that consists of a system of laboratories linked to a net­ work of POC testing sites, with clinical pathways that are optimized to take full advantage of the test results being available within a single patient visit.

4.2 ­Introduction HIV is a global epidemic which has crossed cultures and countries, races and ages. There has been huge progress in the diagnosis and treatment of HIV over the past dec­ ade, but the infection continues to spread and HIV incidence remains high. In 2016 there were an estimated 1.8 million new HIV infections and 1 million deaths from acquired immune deficiency syndrome (AIDS), most of which were in resource‐limited settings, with the majority in sub‐Saharan Africa (UNAIDS 2017). In 2014 the UN launched the 90‐90‐90 goals with the aim that by 2020, 90% of all people living with HIV will know their status, 90% of people diagnosed with HIV infection will receive sus­ tained antiretroviral treatment (ART) and 90% of all people receiving ART will have viral suppression (UNAIDS 2014). Accessible high quality diagnostics are critical to achieving these global targets and rapid tests that can be performed at the POC allow HIV programs to extend access to testing outside of laboratory settings. With most countries committing to attaining the United Nations’ Sustainable Development Goals (SDGs), empowering communities by increasing access to testing so that no one is left behind is an important priority. In this Chapter we will discuss 1) The challenges of delivering HIV care in resource‐limited settings and the diagnostic tests needed to achieve the 90‐90‐90 goals 2) Recent advances in POC tests for HIV diagnosis and monitoring, the impact they have and the remaining challenges, and 3) What is needed to revolutionize healthcare delivery to help countries achieve their 90‐90‐90 targets toward universal access to healthcare as part of the SDGs.

4.3 ­Diagnostic Tests in Resource‐Limited Settings 4.3.1  Challenges of Healthcare Delivery in Resource‐Limited Settings High quality tests are commercially available for the diagnosis of most infectious dis­ eases but they are neither affordable nor accessible to patients in resource‐limited set­ tings. Conventional testing for HIV has routinely involved laboratory‐based tests performed using large expensive equipment that requires a steady source of electricity, sophisticated laboratory infrastructure and highly trained laboratory technicians.

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It was recognized early in the HIV epidemic that diagnostic tests must be made more accessible and affordable so that they can be performed closer to the patient (for example, at the POC) with the potential to: ●●

●●

●● ●● ●●

Expand testing coverage by decentralizing testing to health facilities at different levels of the healthcare system. Allow same‐day testing and results to ensure earlier initiation of treatment and link­ age to care. Allow treatment monitoring where needed. Reduce loss to follow up across the testing‐treatment cascade. Empower health workers to deliver immediate care at every level. Two key aspects for healthcare delivery in resource‐limited settings are that

●●

●●

The tests need to be easy to use so that healthcare workers at all levels of the health­ care system can perform these tests with minimal training. They can be stored without refrigeration for months, and preferably for one– two years, without impacting their accuracy and quality.

These qualities are captured by the ASSURED criteria which stands for Affordable, Sensitive and specific, User‐friendly, Rapid and robust, Equipment free and Deliverable to end‐users, and guides target features of POC diagnostic tests (Mabey et al., 2004). The diagnosis of HIV may be made by either detecting the virus in the blood follow­ ing infection using a molecular assay or waiting for the body’s immune system to pro­ duce antibodies in response to the infection and using serological assays to detect HIV antigen or antibody. Since most infected individuals are not aware of when they become infected and remain asymptomatic for many years, diagnostic tests to detect antibodies to HIV are a highly effective way of diagnosing HIV (Zhang and Versalovic 2002). The first generation of POC tests for HIV were rapid diagnostics tests (RDTs) that detected antibodies to HIV‐1 and ‐2 in 15 minutes using finger‐pricked whole blood samples. The tests were designed as immunochromatographic assays in a lateral flow assay format and required very minimal training to perform three simple steps  – ­collecting the specimen, performing the testing and reading the result. The WHO has pre‐qualified 15 of these RDTs as fulfilling the criteria set by WHO that will ensure accurate and timely results (WHO updated 2018). These RDTs worked well for identifying infected individuals but other diagnostic tests are needed for delivery of a complete package of care for HIV patients. 4.3.2  Diagnostic Tests Needed to Reach the 90‐90‐90 Targets All of the 90‐90‐90 targets require quality‐assured diagnostic tests to accurately identify HIV‐infected individuals, place them on appropriate treatment, properly manage their care and monitor their viral load to ensure viral suppression. Currently, we are only at 70% of the first UN 90 target with a huge gap and substantial challenges in ensuring diagnostic tests are available to all who need them (Table 4.1) (UNAIDS 2017, 2018). 4.3.2.1  The First 90

The first 90 requires all people at risk to be tested and given a diagnosis. However, test­ ing is not available in all settings across the world. Results from laboratory‐based testing may take a long time to reach the patient, leading to significant losses to follow up.

4.3  Diagnostic Tests in Resource‐Limited Settings

Table 4.1  Diagnostic tests needed for each of the 90‐90‐90 targets and challenges. Cohort

Targets

Laboratory tests

POC tests

Challenges

1st 90

90% of people living Immunoassays with HIV know their status

Rapid tests for adults widely available

Adults: stigma, risk perception. Infants: limited access to virologic diagnosis

2nd 90

90% of people diagnosed with HIV are on ART

No test required if test and treat; otherwise, use CD4 tests to determine eligibility

POC CD4 test implementation stalled in many countries as test and treat is being scaled up

Access to POC CD4 testing critical for patients with advanced disease

3rd 90

90% of those on ART are virally suppressed

Viral load (VL) testing only available in national reference laboratories

Limited availability for POC VL tests

Limited access to VL monitoring lack of awareness of ongoing transmission

Many at‐risk individuals may not come forward for testing because of stigma or the perception that they are not at risk. There are ongoing efforts to allow self‐testing in order to overcome these challenges. Lack of access to timely diagnosis and treatment for infants born to HIV‐positive women is a critical barrier in reaching the first 90 for many low‐ and middle‐income countries (LMICs). As maternal antibodies persist in the blood of infants for around 12–18 months, the diagnosis of HIV in the infant must involve detection of the virus itself by a molecular assay such as polymerase chain reaction (PCR). RDTs used in adults may incorrectly diagnose the child as HIV‐positive when maternal antibodies are detected. Previously, early infant diagnosis (EID) involved conventional laboratory molecular assays, which require large expensive equipment and trained personnel. In many LMICs where there is limited access to laboratories, access to infant testing entails  sending blood samples to centralized laboratories with very long turnaround times from testing to diagnosis and initiation on ART. This results in high rates of loss to follow up (Sibanda et al. 2013). Because studies have shown that 50% of HIV‐infected children will die before their 2nd birthday without treatment, with the highest peak of mortality being in the first few months of life (Newell et al. 2004), this delay in diagnosis dramatically affects mortality. In 2015 it was estimated that only 51% of HIV‐exposed infants were tested for HIV within the first two months of life (UNAIDS 2015), resulting in long delays in treatment initiation despite the evidence that early ART in the first few months of life reduces mortality by 75% (Violari et al. 2008). Overall, there is a critical need for new and novel ways of early infant HIV testing that can accurately and rapidly identify infected infants and link them immediately to care and treatment (Ferrand 2017). In 2014 WHO called for elimination of mother‐to‐child transmission of HIV (EMTCT) (WHO 2014) requiring diagnosis and treatment of all HIV‐infected pregnant women. However, many countries have not yet been able to meet these targets and ongoing transmissions from mother‐to‐child still continues. There were 150 000 new infants diagnosed with HIV in 2015, and although this number

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has decreased over time, the detrimental effects of HIV in children if not diagnosed early and started on treatment have been well‐described (UNICEF 2016c). POC EID technology that allows for faster delivery of results, potentially on the same day of sam­ ple collection, and therefore earlier ART initiation, is needed to reduce loss to follow up across the diagnostic and treatment cascade and to prevent mortality from delayed treatment. 4.3.2.2  The Second 90

Although the WHO guidelines changed in 2014 to advise that all people with HIV should be initiated on ART (“Test and Start” or “Universal Test and Treat”), this is not possible in most LMICs with limited access to affordable HIV drugs. These countries still need to rely on CD4 testing to prioritize eligibility for treatment (Peeling et  al. 2015). Implementation of POC CD4 testing has stalled in some countries as the Test and Start option is being scaled up, often leaving patients in rural areas without access to CD4 testing. Worldwide it is estimated that 30–50% of HIV patients already have advanced disease at presentation (WHO 2017d; Waldrop et al. 2016). For these patients, POC CD4 test­ ing is needed to determine if they need prophylaxis against opportunistic infections (WHO 2017a). 4.3.2.3  The Third 90

The third 90 requires lifelong monitoring to ensure the ongoing efficacy of treatment and to immediately identify treatment failure in order to initiate further treatment. A positive viral load can trigger investigation into treatment compliance, and where there is true treatment failure, the patient should be switched to a different drug regimen (WHO 2017b). Viral load testing is traditionally performed using quantitative molecu­ lar assays that require sophisticated laboratory equipment and highly trained labora­ tory technicians. They are expensive and usually only available in national reference laboratories. In many settings, HIV patients are either not monitored for viral load or dried blood spots are collected and sent to central laboratories for viral load testing. This process results in long delays in return of results to rural health centers. Patients often stay on ineffective drug regimens, allowing onward transmission, or become lost to follow‐up across the treatment cascade. Having viral load assays that can be per­ formed at district level hospitals or health facilities is a priority (UNAIDS 2017).

4.4 ­Challenges of Using Rapid and Point‐of‐Care Testing Within the Context of the Healthcare System The diagnostic tests identified above need to be made available where they are needed and fit within, and complement, a complex and often fragmented healthcare system, with many other obstacles beyond testing. The most concentrated number of people living with HIV reside in sub‐Saharan Africa (UNAIDS 2017), where the healthcare system is often overburdened and laboratory infrastructure is limited and underfunded. Having new technologies alone cannot succeed when the health system is stressed because of an already weak infrastructure. Innovation in delivery must accompany technological innovation so that the introduction and scale up of new diagnostic tests can improve patient outcomes while strengthening healthcare systems.

4.5  Recent Advances in HIV Diagnosis and Monitoring and Their Impact

HIV TECHNOLOGY STRENGTHS

WEAKNESSES

PCR TEST/ANTIGEN ASSAY • Gold standard for children < 18 months • High specificity/sensitivity • DBS samples possible

PCR TEST/ANTIGEN ASSAY • Complex • Weak systems to transport DBS to referral laboratories • DBS result reporting can be slow

NEAR POC/CONVENTIONAL TECHNOLOGY • Table top technology • Higher throughput than POC • Use of existence lab set up

POC TECHNOLOGY • Portable light technology • Minimal training and maintenance requirements • No specialised laboratory set-up needed

Tertiary Healthcare Level

Secondary Healthcare Level

Primary Healthcare Level

NEAR POC/CONVENTIONAL TECHNOLOGY • Might need additional equipment such us centrifuge • Reagents might require cold chain • Testing procedure might be more than “plug and play” POC technology POC TECHNOLOGY • May be lower throughput • More testing sites to manage the supply chain, QA, training, service and maintenance, testing data.

Figure 4.1  A schematic diagram of types of HIV testing within each level of the healthcare system. Source: Taken from UNICEF: Accelerate access to innovative point-of-care (POC) HIV diagnostics: CD4, EID and VL 2016 (UNICEF 2016d).

While RDTs for the serological diagnosis of HIV can be used at all levels of the health­ care system, the majority of device‐based POC/near‐POC assays such as CD4, EID and viral load monitoring are too expensive to be made available everywhere. Although these near‐POC assays are sample‐in‐answer‐out or “plug and play” devices, they still require more extensive training and maintenance than RDTs. For optimal usage, cost‐ effectiveness and revolutionary impact on patient care, POC tests are best placed at district level health facilities and hospitals, in clinics or hospitals in urban areas to com­ plement existing laboratory infrastructure, or at central testing hubs each providing testing at a group of sites (Diallo et  al. 2017). Countries need to strategically place devices taking into account patient load, geographical locations, device characteristics and existing laboratory infrastructure (Diallo et  al. 2017) and, in parallel, determine how this will strengthen the laboratory–clinic interface (UNICEF 2016d) (Figure 4.1).

4.5 ­Recent Advances in HIV Diagnosis and Monitoring and Their Impact 4.5.1  HIV Self‐Testing and Multiplex Testing HIV self‐testing (HIVST) using either oral or blood‐based testing is the latest advance­ ment in bringing testing closer to the patient. With self‐testing, the person performs the HIV diagnostic test and interprets the results in private. In 2015 WHO released

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4  Revolutionizing HIV Healthcare Delivery Through Rapid and Point‐of‐Care Testing

guidance to support the implementation and scale‐up of ethical, effective, acceptable and evidence‐based approaches to HIVST (WHO, 2016a). This approach will still require appropriate quality assurance and monitoring to determine whether this intervention will contribute to closing the testing gap and achieving the United Nations’ 90–90–90 global goals. Multiplex testing allows for HIV testing to be combined with other testing that is appropriate for HIV‐infected patients, including, for example, tuberculosis, syphilis, hepatitis B and hepatitis C. This approach would presumably provide a larger catch­ ment of testing and faster results, and would perhaps be less costly for the healthcare system. Studies are ongoing to determine if multiplex testing can increase overall diag­ nosis and early detection and increase efficiency of the healthcare system. 4.5.2  Early Infant Diagnosis of HIV In recent years there has been an increase in EID testing and expansion of the labora­ tory network with the use of dried blood spots (DBS). Filter paper is used to collect blood specimens in remote areas and then transport them dried at room temperature to the laboratory for testing. However, in 2015 only 51% of at‐risk infants received an HIV test before two months of age (UNAIDS 2016), highlighting the need for a new strategy to revolutionize the healthcare of infants. Alongside the WHO call for EMTCT of HIV, over the past few years there has been a push for the development of POC diag­ nostics for EID. In 2015 UNITAID published the diagnostic pipeline of EID technolo­ gies (UNITAID 2015) (Figure 4.2). These devices may be used near or at the POC and are able to process specimens and provide results the same day. These POC nucleic acid testing devices are able to per­ form qualitative EID molecular testing, traditionally performed in centralized laborato­ ries, in almost any setting by trained healthcare workers using portable or semi‐portable devices. The quality of EID POC testing has been evaluated in both laboratory and field set­ tings. Four POC EID technologies have received CE‐IVD (Conformité Européene In  Vitro Diagnostics) approval and two POC EID technologies have met WHO pre­ qualification requirements: Alere q HIV 1/2 Detect and Cepheid Xpert HIV‐1 qual (WHO 2017d). In 2015 the EID Consortium was established to bring together global expertise in the fields of public health, HIV diagnostics and infant health in order to overcome the challenges of diagnosing and treating infant HIV (www.eidconsortium. org). The first priority for the EID Consortium was to determine the field performance of POC EID devices through a pooled analysis of existing data for the first two products ready for evaluation: the Alere q HIV‐1/2 Detect and the Cepheid GeneXpert HIV‐1 qual. Data from nine independent field evaluations from six countries were pooled (Carmona et al. 2016). The results showed that both the Alere q HIV‐1/2 Detect and the Cepheid Xpert HIV‐1 qual performed well in field testing with high sensitivity and specificity, comparable to laboratory testing and thus supported the use of these POC EID devices (WHO 2017c). The impact on infant case finding and treatment initiation has been investigated in pilot studies from Mozambique and Malawi (Jani et al. 2016; Mwenda 2016). Both stud­ ies found that POC EID significantly reduced the turnaround time of results when com­ pared with standard of care conventional testing. The majority received same‐day results, and consequently POC EID allowed earlier initiation of ART. Additionally, the

Under development

EasyQ®

HIV-1 v2.0 bioMerieux DBS+CE Mark - 2009

TaqMan®

HIV-1 v2.0 DBS/FVE Roche (DBS) RealTime HIV-1 DBS Abbott

Roche/lquum

Ustar

Wave 80

Xpert® HIV-1 VL Cepheid CE Mark

Daktari

AlereTM q VL Alere

Micronics

Savanna VL NWGHF

SAMBA I Semi-Q VL DDU/Cambridge Kenya, Malawi, Uganda

Nanobiosim

Truelab Uno Molbio DX India

2014

Lumora

2015

* Reported July 2015 - timeline and sequence may change + Dried blood spot assay CE Marked

ZIVA RT Cavidi

Aptima® HIV-1 Quant DBS Hologic

2016 no specific market launch date

Figure 4.2  HIV/AIDS point‐of‐care viral load technologies in the pipeline. Source: UNITAID. HIV/AIDS Diagnostics Technology Landscape, October 2015. http://www.unitaid.org/assets/UNITAID_HIV_Nov_2015_Dx_Landscape‐1.pdf Accessed on 18th February 2018. Abbreviations used: DBS, dried blood spot, CE, Conformité Européenne, meaning European Conformity. (CE marking is a certification mark that indicates conformity with health, safety, and environmental protection standards for products sold within the European Economic Area.)

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4  Revolutionizing HIV Healthcare Delivery Through Rapid and Point‐of‐Care Testing

study in Malawi showed an overall increase in ART initiation (Mwenda 2016) and the results from Mozambique demonstrated improved ART retention rates, reducing loss to follow up (Jani et al. 2016), and addressing a critical gap given the extensive loss to follow up across the EID cascade(Siyanda et al. 2013). Mwenda et al. also demonstrated that POC EID devices were acceptable to healthcare workers and patients, although some of the near POC devices could not be used in all health facilities (Maenad 2016). Provider acceptability of using POC EID devices has been further reinforced by a field implementation study in South Africa (Dunning et al. 2017). The WHO have supported the use of POC or near POC nucleic acid testing technolo­ gies as described in the 2016 WHO Consolidated Guidelines on the use of antiretroviral drugs for treating and preventing HIV infection (WHO 2013). In 2017 the WHO rec­ ommended the rapid national regulatory approval and initiation of scale up of these devices and incorporation of POC EID into National HIV Care and Treatment Guide­ lines (WHO 2017c). However, there are concerns about the high cost and shelf‐life of cartridges, the supply chain and availability of local technical support for repairs. There are also challenges to sustainability and to having the POC equipment accessible to every infant (birth testing). The different POC machines are not all for use in primary healthcare facilities and district hospitals may serve as the best location for balancing distance and the cost of running the test. Individual strategies for different countries should be developed for prioritizing the POC devices and need to be based on patient throughput and maximization of POC EID utilization. In Mozambique a study showed that a prototype POC p24 Ag detec­ tion test (the LYNX), despite its low sensitivity of 72%, had the potential to provide test results for up to 81% more patients compared to sending dried blood spots to laboratories for testing (Maggi et al. 2017). This prototype POC p24 assay is feasible for use in primary healthcare settings and is more affordable than near‐POC molecu­ lar tests for EID. 4.5.3  POC CD4 Testing for Managing HIV Patient Care 4.5.3.1  Before the Initiation of ART

The use of POC diagnostic technologies significantly improves retention in the pre‐ ART care cascade. POC CD4 testing can reduce time to result from ten days to less than one day on average (Vojnov et al. 2016). In Mozambique POC CD4 testing reduced loss to follow‐up before ART initiation by 50% (Jani et al. 2011). POC CD4 testing is still being used to initiate treatment in many countries. A qualitative study in Uganda found that diagnostic tests, such as POC testing, combined with interventions to change pro­ vider behaviors enhanced uptake of innovations targeting the HIV cascade in clinical settings (Semitala et al. 2017). In Namibia POC CD4 testing was feasible and effective when task‐shifted to lay health workers. The rollout of POC CD4 testing improved access to CD4 testing and retention in care between HIV diagnosis and ART initiation in LMICs (Kaindjee‐Tjituka et al. 2017). 4.5.3.2  The Use of the CD4 Test for Early HIV Disease

The landscape for diagnostic tests, and particularly those performed at the primary POC is continually rapidly changing. In 2010 WHO updated its recommendations for monitoring treatment effectiveness in HIV patients on antiretroviral therapy. Until that year the international recommendation was a combination of clinical monitoring

4.5  Recent Advances in HIV Diagnosis and Monitoring and Their Impact

and the CD4+ T cell (CD4) count. However, other research showed that monitoring viral load was an earlier and more sensitive way to identify treatment failure (WHO 2013). In 2016 the WHO Consolidated Guidelines on the use of Antiretroviral Drugs for Treating and Preventing HIV infection recommended that all patients who tested posi­ tive for HIV initiate antiretroviral therapy, regardless of the CD4 count, and empha­ sized that viral load monitoring should be used to determine treatment failure (WHO 2013). While CD4 monitoring is being phased out in many places in favor of annual viral load monitoring, the WHO treatment guidelines still recommend the use of CD4 testing for clinical management (WHO 2017a). CD4 count is the best predictor for dis­ ease status and immediate risk of death and thus should be used to identify those who have advanced HIV disease. Patients who are unstable or have advanced HIV disease should have a CD4 test every six months until stable. 4.5.3.3  The CD4 Test for Advanced HIV Disease

The WHO Guidelines for Managing Advanced HIV Disease and Rapid Initiation of Antiretroviral Therapy defines a role for CD4 testing in identifying and managing patients with advanced HIV disease through a package of services (WHO 2017a). Performing a CD4 test at baseline is important because, even though many countries have adopted the test and start approach, the percentage of patients starting ART with advanced disease has not changed and new data suggest that a high proportion of  patients with advanced disease are asymptomatic. Data from the International Epidemiology Databases to Evaluate AIDS (IeDEA) cohort suggest that in some set­ tings more than 50% of people are starting ART with advanced HIV disease (Avila et al. 2014). The WHO Guidelines for Managing Advanced HIV Disease and Rapid Initiation of Antiretroviral Therapy uses a CD4+ T cell threshold of